Compounds useful for the treatment and/or care of the skin, hair, nails and/or mucous membranes

ABSTRACT

A compound of formula (I) R 1 -W m -X n -AA 1 -AA 2 -AA 3 -AA 4 -AA 5 -AA 6 -Y p -Z q -R 2 , a stereoisomer and/or cosmetically acceptable salt thereof, and a method of treatment using the compound are described. In the compound, AA 1  is Asp, Gly, Asn, Gln, Ala or no amino acid; AA 2  is Val, Ile, Leu or Ala; AA 3  is Tyr, Phe, Trp, Lys, Arg or His; AA 4  is Lys, Arg, His, Pro or Val; AA 5  is Asn, Asp, Gln or no amino acid; AA 6  is Thr, Ala, Ser or no amino acid. The compounds are useful for the treatment of the symptoms of skin aging and, in particular, for the treatment of skin wrinkles, the treatment of a sagging appearance of the skin, and/or the reduction of facial asymmetry.

This application claims the priority of International ApplicationPCT/IB2020/051021, filed Feb. 10, 2020, and EP 19382092.5, filed Feb.10, 2019, from which the PCT application claims priority, thedisclosures of which are incorporated herein in their entireties byreference.

FIELD OF THE INVENTION

The invention relates to compounds useful for the treatment and/or careof the skin, hair, nails and/or mucous membranes. In particular, thecompounds are useful for the prevention of skin aging and, inparticular, for the treatment and/or prevention of skin wrinkles, thetreatment and/or prevention of a sagging appearance of the skin, and/orthe reduction and/or prevention of facial asymmetry. The inventionextends to compositions comprising the compounds and methods oftreatment using the compounds.

BACKGROUND OF THE INVENTION

The effects of aging play a major role in skin appearance. The moststriking signs of facial aging are wrinkles and a sagging appearance ofthe face. With the passing of time: the epidermis and connective tissueof the skin become weak; facial muscular firmness diminishes; theepidermis begins to loosen and drop; the natural folds in the skin inthe cheek, neck, and chin area change; and there is a redistribution andloss of facial fat.

In particular, a loss of facial muscular firmness is associated withmuscle aging. Muscle aging is a well-known process which can start inhumans when they are around 40 years old and it accelerates in lateryears. The resultant loss of muscle mass (muscle tone) can give the facea loose, sagging appearance. The jawline loses its contour, and theprofile of the face becomes less defined.

Different methods to improve facial muscular firmness have beenproposed. One of the most popular methods for reducing facial sagging isthe face-lift. The face-lift, also known as rhytidectomy, is a cosmeticsurgical procedure to reduce the sagging or folds of skin on the cheeksand jawline as well as other changes in the shape of the face that takeplace with age. During a face-lift, a flap of skin on each side of theface is pulled back, and tissues below the skin are surgically alteredto return the contour of the face to a more youthful shape.Nevertheless, face-lifts can be associated with different complicationsand risks. Like any other type of surgery, a face-lift poses a risk ofbleeding, infection and an adverse reaction to anesthesia. Some otherrisks include hematoma, scarring, nerve injury, hair loss and skin loss,among others. Moreover, the results of face-lifts are not permanent.With age, the facial skin may begin to droop again. In general, aface-lift can be expected to last 10 years.

Not surprisingly, there is a growing interest in alternativenon-invasive methods to reduce face sagging. One of the most promisingones is electrical stimulation. Electronic muscle stimulation (EMS) hasbeen used as an alternative intervention to improve muscle recovery,improvement of muscle structure and function in multiple biomedicalfields. [Kern, H. et al “Electrical stimulation counteracts muscledecline in seniors”, (2014), Frontiers in Aging Neuroscience, Vol6(189), pp. 11-11]. There are four main types of treatment, that differin the type of electric current they use: galvanic treatment,neuromuscular electrical stimulation (NMES) (also known as Faradictreatment), micro-current electrical neuromuscular stimulation (MENS)and high-frequency treatment.

MENS is distinguished by the use of extremely small electrical currents(i.e., millionths of an amp, e.g., 300-500 μA) which are hardlyperceptible, but mimic the body's own bio-electric currents. MENS isthus not designed for medical use, but for cosmetic non-therapeuticbeauty treatment for improving skin rejuvenation as an effective,non-invasive, and inexpensive technique to fight against skin agingappearance [Goldbert, A. et al. “Skin Rejuvenation with Non-InvasivePulsed Electric Fields”, (2015), Nature Scientific Reports, Vol5(10187), pp. 1-18; Seniee, F. et al. “Consider of Micro-Current'seffect to variation of Facial Wrinkle trend, Randomized Clinical TrialStudy”, (2012), Life Science Journal Vol 9(3), pp. 1184-1189]. Bystimulating the skin cells in a particular way, it is possible to reducethe wrinkles and sagging of the skin.

On a cellular level MENS is also known to stimulate collagen and elastinproduction. Collagen is the most abundant protein in the connectivetissue of the skin and forms a mesh-like structure that helps to supportnew cells as they grow, while providing needed flexibility. One ofwell-recognized characteristics of aging is sagging of the skin.Increase of collagen synthesis is considered beneficial to reduce agingsigns. Collagen synthesis declines with aging leading to a loss of skinfirming and contributing to appearance of wrinkles in older people[Varani, J. et al. “Decreased Collagen Production in ChronologicallyAged Skin: Roles of Age-Dependent Alteration in Fibroblast Function andDefective Mechanical Stimulation”, (2006), American Journal ofPathology, Vol. 168 (6), pp. 1861-1868]. Therefore, MENS can improve thefirmness and toning of facial skin.

Nevertheless, treatment using MENS attracts some disadvantages. Forinstance, the intensive levels of the electrical currents may depend onindividual skin thickness. Generally, if health is deteriorated or thephysical state changes, the microcurrent flowing within the human bodybecomes weak. Skin thickness is subjected to changes of age or externalfactors, and thus there is high intra- and interindividual variability.In some cases, poor electrical contact between the electrode and thesurface being treated results in the user feeling discomfort and pain,and in extreme cases can result in skin irritation. Some MENS devicesuse electrodes and adhesive gels to improve the conductivity, but thisis expensive and inconvenient on, e.g., the face because there is noallowance for movement of the electrodes once they have been positioned.Further, depending on the device, it can be difficult to preciselyfollow the outline of the surfaces of the body being treated and this isa problem as the stimuli should be able to address to a precise area.For example, some devices require the use of a mirror in order to beable to locate the wands of the device on the appropriate parts of theface and squeeze or lengthen the skin. Finally, some potential usershave a negative preconception of MENS treatment, i.e., prejudicesagainst using electricity on their face, for example, as a daily beautytreatment.

There is a need to provide alternative methods for alleviating orpreventing the signs of skin aging for example, for improving skin toneand firmness and/or for reducing a sagging appearance of the skin. Thereis a need to provide such a method that overcomes the problemsassociated with known methods such as face-lifts or MENS. There is aneed to find novel active compounds that can alleviate or prevent thesigns of skin aging. In particular, there is a need to find novel activecompounds that can prevent or reduce skin wrinkles and/or a saggingappearance of the face.

The present invention sets out to meet some or all of these needs and tosolve some or all of the above-identified problems.

SUMMARY OF THE INVENTION

In a first aspect, the invention provides a compound represented byformula (I):

R₁-W_(m)-X_(n)-AA₁-AA₂-AA₃-AA₄-AA₅-AA₆-Y_(p)-Z_(q)-R₂   (I),

-   -   a stereoisomer and/or cosmetically acceptable salt thereof,        wherein:    -   AA₁ is Asp, Glu, Asn, Gln, Ala, Gly or no amino acid;    -   AA₂ is Val, Ile, Leu or Ala;    -   AA₃ is Tyr, Phe, Trp, Lys, Arg or His;    -   AA₄ is Lys, Arg, His, Pro or Val;    -   AA₅ is Asn, Asp, Gln or no amino acid;    -   AA₆ is Thr, Ala, Ser or no amino acid;    -   W, X, Y and Z are each independently any amino acid;    -   m, n, p and q are each independently 0 or 1;    -   m+n+p+q is less than or equal to 2;    -   R₁ is selected from the group consisting of H, a polymer derived        from polyethylene glycol, a non-cyclic aliphatic group,        alicyclyl, heterocyclyl, heteroarylalkyl, aryl, aralkyl and        R₅—CO—, wherein R₅ is selected from the group consisting of H, a        non-cyclic aliphatic group, alicyclyl, aryl, aralkyl,        heterocyclyl and heteroarylalkyl;    -   R₂ is selected from the group consisting of —NR₃R₄, —OR₃, —SR₃,        wherein R₃ and R₄ are independently selected from a group        consisting of H, a polymer derived from polyethylene glycol, a        non-cyclic aliphatic group, alicyclyl, heterocyclyl,        heteroarylalkyl, aryl and aralkyl; and    -   R₁ and R₂ are not amino acids.

In particular, the invention provides compounds represented by formula(I) wherein, when AA₅ Asn, Asp or Gin, AA₁ is Ala, Gly or no amino acid;AA₂ is Val, Ile or Leu; AA₃ is Lys, Arg or His; AA₄ is Pro or Val; AA₆is Thr, Ala, Ser or no amino acid, with the proviso that AA₁ isdifferent from AA₆. Optionally, or in addition, the invention providescompounds represented by formula (I) wherein, when AA₅ is no amino acid,AA₁ is Asp, Glu, Asn or Gin; AA₂ is Val, Ile, Leu or Ala; AA₃ is Tyr,Phe or Trp; AA₄ is Lys, Arg or His; and AA₆ is no amino acid.

It has been found that compounds of the invention are effective inupregulating the expression of muscle blind-like 1 (MBNL1). MBNL1 is ahighly conserved RNA-binding protein, which plays an important role inthe process of muscle differentiation and maintenance. An increase ofMBNL1 protein in fibroblast cells activates their trans-differentiationprocess to myofibroblasts, a cell-type able to release a higher amountof extracellular matrix proteins, like collagen, elastin andfibronectin. This increase in myofibroblasts results in an increase incollagen in the skin, resulting in a firming effect on the skin. Thus,the compounds of the invention are useful for alleviating and/orpreventing problems associated with loss of muscle mass (muscle tone)due to muscle aging, such as an appearance of facial sagging. Further,the compounds of the invention can be used for a beauty treatment thatexerts a lifting effect of the skin through chemical mechanisms, similarto the effect of physical treatments such as electric stimulationmicrocurrents, but without the inconveniences of the latter. Inaddition, compounds of the invention have been found to be effective ininhibiting noradrenaline release in the skin and in increasing theamount of lipids in adipose cells. These further indicate theirusefulness as skin antiaging agents.

In another aspect, the invention provides a cosmetic compositioncomprising a compound of formula (I), its stereoisomers and/or itscosmetically acceptable salts, together with at least one cosmeticallyacceptable excipient or adjuvant.

In another aspect, the invention provides the use of a compound offormula (I), its stereoisomers and/or its cosmetically acceptable salts,or a composition comprising a compound of formula (I), its stereoisomersand/or its cosmetically acceptable salts, for the treatment and/or careof the skin, hair, nails and/or mucous membranes. In particular, theinvention provides the use of a compound of formula (I), itsstereoisomers and/or its cosmetically acceptable salts, or a cosmeticcomposition comprising a compound of formula (I), its stereoisomersand/or its cosmetically acceptable salts, for the cosmetic,non-therapeutic treatment and/or care of the skin, hair, nails and/ormucous membranes. The cosmetic, non-therapeutic treatment and/or carecan be: the prevention or the treatment of the symptoms of skin aging;the treatment and/or prevention of skin wrinkles; the stimulation ofcollagen synthesis and/or prevention of collagen loss; the improvementor maintenance of skin firmness; the treatment and/or prevention of asagging appearance of the skin; the treatment or prevention of facialasymmetry; the increase of the volume of adipose tissue; and/or theprevention and/or alleviation of effects of adipose tissue loss.

In another aspect, the invention provides a method of treatment and/orcare of the skin, hair, nails and/or mucous membranes in a subjectcomprising administering an effective amount of a compound of formula(I), its stereoisomers and/or its cosmetically or pharmaceuticallyacceptable salts, or a composition comprising same, to the subject. Inparticular, the invention provides a method of cosmetic, non-therapeutictreatment and/or care of the skin, hair, nails and/or mucous membranesin a subject comprising administering a cosmetically effective amount ofa compound of formula (I), its stereoisomers and/or its cosmeticallyacceptable salts, or a cosmetic composition comprising same, to thesubject. Typically, the compound will be administered topically. Thecosmetic, non-therapeutic treatment and/or care can be: the preventionor the treatment of the symptoms of skin aging; the treatment and/orprevention of skin wrinkles; the stimulation of collagen synthesisand/or prevention of collagen loss; the improvement or maintenance ofskin firmness; the treatment and/or prevention of a sagging appearanceof the skin; and/or the treatment or prevention of facial asymmetry theincrease of the volume of adipose tissue; and/or the prevention and/oralleviation of effects of adipose tissue loss.

In another aspect, the invention provides a kit for use in a cosmetic,non-therapeutic method of treatment and/or care of the skin comprising:

-   -   (i) a composition comprising Botulinum toxin;    -   (ii) optionally a composition comprising        Ac-Glu-Glu-Met-Gln-Arg-Arg-NH₂ (Ac-[SEQ ID NO. 41]-NH₂; and    -   (iii) a cosmetic composition comprising a compound of formula        (I).

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows percentages of MBNL1 protein present in human skeletalmuscle cells (based on total protein content of the human skeletalmuscles cells) measured using a time resolved fluorescence energytransfer assay. The measurements are made on samples of human skeletalmuscles cells treated with a compound of the invention and for a controlsample of human skeletal muscles cells not treated with a compound ofthe invention (Example 7). Abbreviations: BC, basal control.

FIG. 2 shows levels of MBNL1 protein present in human dermal fibroblastsmeasured using an immunofluorescence assay. The measurements are made onsamples of human dermal fibroblasts treated with a compound of theinvention and for a control sample of human dermal fibroblasts nottreated with a compound of the invention (Example 8). Abbreviations: BC,basal control.

FIG. 3 shows levels of muscle mass loss in human skeletal muscle cellsmeasured using an immunofluorescence assay. The measurements are made onsamples of human skeletal muscle cells treated with a compound of theinvention and for a control sample of human skeletal muscle cells nottreated with a compound of the invention (Example 9). Abbreviations: BC,basal control.

FIG. 4 shows percentage of muscle mass loss in human skeletal musclecells measured using an immunofluorescence assay. The measurements aremade on samples of human skeletal muscle cells treated with tumornecrosis factor alpha (TNFα) and either (i) treated with a compound ofthe invention or (ii) not treated with a compound of the invention.Results are also compared with human skeletal muscle cells that areneither treated with TNFα nor treated with a compound of the invention(Example 10). Abbreviations: BC+TNF, Basal control with 20 mg/ml ofTNFα; BC, Basal control.

FIG. 5 shows levels of type 1 collagen on human dermal fibroblasts asdetermined by an alpha-ELISA assay (Example 11). The measurements aremade on samples of human dermal fibroblasts treated with a compound ofthe invention and a basal control that is not treated with a compound ofthe invention. Abbreviations: % COL, Percentage of Collagen type I; BC,basal control.

FIG. 6 shows levels of noradrenaline release on human neuroblastoma cellline ss determined using and immunofluorescence assay. The measurementsare made on samples of human neuroblastoma cell line treated with acompound of the invention and a basal control that is not treated with acompound of the invention (Example 12). Abbreviations: NA,noradrenaline; BC, basal control.

FIG. 7 shows levels of lipid accumulation in human subcutaneouspre-adipocytes as determined by fluorescent staining. The measurementsare made on samples of a coculture of young and old pre-adipocytes thathave been treated with a compound of the invention or that have not beentreated with a compound of the invention. Results are also compared witha culture of old pre-adipocytes. Abbreviations: % LA, Percentage oflipid accumulation; CC, Coculture control; YC, young control; OC, oldcontrol.

DETAILED DESCRIPTION OF THE INVENTION Definitions

In the context of this invention “skin” is understood to be the layerswhich comprise it, from the uppermost layer or stratum corneum to thelowermost layer or hypodermis, both inclusive. These layers are composedof different types of cells such as keratinocytes, fibroblasts,melanocytes, mast cells, neurones and/or adipocytes among others. Theterm “skin” also comprises the scalp. The term “skin” includes the skinof mammals and includes human skin. Likewise, the terms “hair, nails andmucous membranes” include the hair, nails and mucous membranes ofmammals, for example humans.

The term “treatment”, as used herein and when it is not accompanied bythe qualifications “cosmetic, non-therapeutic” refers to therapeuticmethods including methods directed to the administration of a compoundaccording to the invention to alleviate or eliminate a disease ordisorder, or to reduce or eliminate one or more symptoms associated withsaid disease or disorder. The term “treatment”, when it is notaccompanied by the qualifications “cosmetic, non-therapeutic”, alsocovers methods of therapy directed to alleviating or eliminatingphysiological consequences of the disease or disorder.

When the terms “treatment” and “care” are accompanied by thequalifications “cosmetic, non-therapeutic”, it means that the treatmentor care has the aim of improving or maintaining the aesthetic appearanceof the skin, hair, nails and/or mucous membranes. In particular, thetreatment can have the aim of improving cosmetic properties of the skin,hair, nails and/or mucous membranes such as, for example and notrestricted to, the level of hydration, elasticity, firmness, shine, toneor texture, which properties affect the aesthetic appearance of theskin, hair, nails and/or mucous membranes. The term “care” in thecontext of this specification refers to the maintenance of properties ofthe skin, hair, nails and/or mucous membranes. Said properties aresubject to being improved or maintained by cosmetic treatment and/orcare of the skin, hair, nails and/or mucous membranes both in healthysubjects as well as in those which present diseases and/or disorders ofthe skin, hair, nails and/or mucous membranes.

The term “inhibition”, as used in this invention, refers to the abilityof a compound of the invention to delay or hinder the appearance ordevelopment of a disease or disorder, or to delay or hinder the changein a cosmetic property of the skin, mucous membranes and/or hair. Theterm “inhibition”, “ ” refers to the ability of a compound of theinvention to inhibit the appearance or development of a disease ordisorder, or to inhibit the change in a cosmetic property of the skin,hair, nails and/or mucous membranes.

In the context of this invention, the term “aging” refers to the changesexperienced by the skin as the result of intrinsic aging process (i.e.,chronoaging) or extrinsic skin aging process induced by environmentalfactors (i.e., through exposure to the sun (photoaging) or toenvironmental agents such as tobacco smoke, extreme climatic conditionsof cold or wind, chemical contaminants or pollutants). In the context ofthe invention, aging includes all the external visible and/orperceptible changes through touch, such as and not restricted to, thedevelopment of discontinuities on the skin such as wrinkles, fine lines,expression lines, stretch marks, furrows, irregularities or roughness,increase in the size of pores, loss of hydration, loss of elasticity,loss of firmness, loss of smoothness, loss of the capacity to recoverfrom deformation, loss of resilience, sagging of the skin such assagging cheeks, the appearance of bags under the eyes or the appearanceof a double chin, among others, changes to the color of the skin such asmarks, reddening, bags or the appearance of hyperpigmented areas such asage spots or freckles among others, anomalous differentiation,hyperkeratinization, elastosis, keratosis, hair loss, orange-peel skin,loss of collagen structure and other histological changes of the stratumcorneum, of the dermis, epidermis, vascular system (for example theappearance of spider veins or telangiectasias) or of those tissues closeto the skin, among others. The term “photoaging” groups together the setof processes due to the prolonged exposure of the skin to ultravioletradiation which result in the premature aging of the skin, and itpresents the same physical characteristics as aging, such as and notrestricted to, flaccidity, sagging, changes to the color orirregularities in the pigmentation, abnormal and/or excessivekeratinization. The sum of various environmental factors such asexposure to tobacco smoke, exposure to pollution, and climaticconditions such as cold and/or wind also contribute to the aging of theskin.

In this description, the abbreviations used for amino acids follow therules of IUPAC-IUB Commission of Biochemical Nomenclature specified inEur. J. Biochem., (1984), 138, 9-37. Thus, for example, Gly representsNH₂—CH₂—COOH, Gly- represents NH₂—CH₂—CO—, -Gly represents —NH—CH₂—COOHand -Gly- represents —NH—CH₂—CO—. Therefore, the hyphen, whichrepresents the peptide bond, eliminates the OH in the 1-carboxyl groupof the amino acid (represented here in the conventional non-ionizedform) when situated to the right of the symbol, and eliminates the H ofthe 2-amino group of the amino acid when situated to the left of thesymbol; both modifications can be applied to the same symbol (see Table1).

TABLE 1 Structures of the amino acid residues, their nomenclature inthree- letter code and nomenclature for the amino acids in one lettercode Name Residue Symbol Residue Arginyl -Arg- R

Lysyl -Lys- K

Glutaminyl -Gln- Q

Tryptophyl -Trp- W

Asparaginyl -Asn- N

Phenylalanyl -Phe- F

Leucyl -Leu- L

Aspartyl -Asp- D

Alanyl -Ala- A

Valyl -Val- V

Isoleucyl -Ile- I

Glycyl -Gly- G

Histidyl -His- H

Prolyl -Pro- P

Tyrosyl -Tyr- Y

Seryl -Ser- S

Threonyl -Thr- T

As used herein, the term “non-cyclic aliphatic group” includes linear(i.e., straight and unbranched) or branched, saturated or unsaturatedhydrocarbyl groups such as alkyl, alkenyl and alkynyl. The non-cyclicaliphatic group may be substituted (mono- or poly-) or unsubstituted.

As used herein, the term “alkyl” includes both saturated linear andbranched alkyl groups, which may be substituted (mono- or poly-) orunsubstituted. The alkyl group is bound to the rest of the molecule by asingle bond. The alkyl group has from 1 to 24, preferably from 1 to 16,more preferably from 1 to 14, even more preferably from 1 to 12, yetmore preferably 1, 2, 3, 4, 5 or 6 carbon atoms. The term “alkyl”includes, for example, methyl, ethyl, isopropyl, isobutyl, tert-butyl,2-methylbutyl, heptyl, 5-methylhexyl, 2-ethylhexyl, octyl, decyl,dodecyl, lauryl, hexadecyl, octadecyl and amyl.

As used herein, the term “alkenyl” refers to a group containing one ormore double carbon-carbon bonds and which may be linear or branched andsubstituted (mono- or poly-) or unsubstituted. Preferably it has 1, 2 or3 double carbon-carbon bonds. If more than one double carbon-carbon bondis present, the double bonds may be conjugated or not conjugated.Preferably the alkenyl group has from 2 to 24, preferably from 2 to 16,more preferably from 2 to 14, even more preferably from 2 to 12, yetmore preferably 2, 3, 4, 5 or 6 carbon atoms. The alkenyl group is boundto the rest of the molecule by a single bond. The term “alkenyl”includes, for example, vinyl (—CH₂═CH₂), allyl (—CH₂—CH═CH₂), prenyl,oleyl, linoleyl groups and similar.

The term “alkynyl” refers to a group containing one or more triplecarbon-carbon bonds and which may be linear or branched, and substituted(mono- or poly-) or unsubstituted. Preferably the alkynyl group has 1, 2or 3 triple carbon-carbon bonds. The triple bonds may be conjugated ornot conjugated. The alkynyl group has from 2 to 24, preferably from 2 to16, more preferably from 2 to 14, even more preferably from 2 to 12, yetmore preferably 2, 3, 4, 5 or 6 carbon atoms. The alkynyl group is boundto the rest of the molecule by a single bond. The term “alkynyl”includes, for example and not restricted to, ethynyl, 1-propynyl,2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, pentynyl, such as1-pentynyl, and similar. The alkynyl group can also contain one or moredouble carbon-carbon bonds, and alkynyl groups include, for example andnot restricted to, but-1-en-3-ynyl and pent-4-en-1-ynyl groups, andsimilar.

The term “alicyclyl” is used herein to cover, for example and notrestricted to, aliphatic cyclic (alicyclic) groups such as cycloalkyl orcycloalkenyl or cycloalkynyl groups. The term “alicyclyl” refers to amonoradical that contains one or more rings of carbon atoms, the ringsmay be saturated (e.g., cyclohexyl) or unsaturated (e.g., cyclohexenyl)provided that they are not aromatic. More specifically alicylic groupscontain three or more, from 3 to 24, from 3 to 12, or from 6 to 12, ringcarbon atoms. The alicyclic group may be a monocyclic, bicyclic, ortricyclic ring system and the rings may be, for example, fused or linkedby a single bond or a linking group such as a methylene or otheralkylene group. The alicyclic group may be substituted (mono- or poly-)or unsubstituted. In one embodiment, the alicyclyl group is a 6 to 12membered ring system which consists of carbon atoms and optionallycontains one or two double bonds.

The term “cycloalkyl” refers to a saturated mono- or polycyclic alkylgroup which may be substituted (mono- or poly-) or unsubstituted. Thecycloalkyl group has from 3 to 24, preferably from 3 to 16, morepreferably from 3 to 14, even more preferably from 3 to 12, yet evenmore preferably 3, 4, 5 or 6 carbon atoms. The cycloalkyl group is boundto the rest of the molecule by a single bond. Cycloalkyl groups include,for example and not restricted to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, methyl cyclohexyl, dimethyl cyclohexyl,octahydroindene, decahydronaphthalene, dodecahydrophenalene and similar.

The term “cycloalkenyl” refers to a non-aromatic mono- or polycyclicalkenyl group which may be substituted (mono- or poly-) orunsubstituted. The cycloalkenyl group has from 5 to 24, preferably from5 to 16, more preferably from 5 to 14, even more preferably from 5 to12, yet more preferably 5 or 6 carbon atoms. The cycloalkenyl group isbound to the rest of the molecule by a single bond. Preferably thecycloalkenyl group contains 1, 2 or 3 double carbon-carbon bonds. Ifmore than one double carbon-carbon bond is present, the double bonds maybe conjugated or not conjugated. Cycloalkenyl groups include, forexample and not restricted to, the cyclopent-1-en-1-yl group andsimilar.

The term “cycloalkynyl” refers to a non-aromatic mono- or polycyclicalkynyl group which may be substituted (mono- or poly-) orunsubstituted. The cycloalkynyl group has from 8 to 24, preferably from8 to 16, more preferably from 8 to 14, even more preferably from 8 to12, yet even more preferably 8 or 9 carbon atoms and is bound to therest of the molecule by a single bond. Preferably the cycloalkynyl groupcontains 1, 2 or 3 triple carbon-carbon bonds, conjugated or notconjugated. Cycloalkynyl groups include, for example and not restrictedto, the cyclooct-2-yn-1-yl group and similar. Cycloalkynyl groups canalso contain one or more double carbon-carbon bonds, including, forexample and not restricted to, the cyclooct-4-en-2-ynyl group andsimilar.

As used herein, the term “heterocyclyl” or “heterocyclic” refers to ahydrocarbon ring system of 3 to 10 members, wherein one or more of theatoms in the ring or rings is a heteroatom (i.e., not a carbon atom).Thus “heterocyclyl” or “heterocyclic” refers a cyclic group in which thering atoms consist of carbon and one or more heteroatoms. To satisfyvalence, the heteroatom may be bonded to H or substituent groups.Preferably from 1, 2 or 3 of the ring carbon atoms are heteroatoms. Eachheteroatom can be independently selected from the group consisting of O,N, S, P and B, or the group consisting of O, N, and S. The heterocyclylgroup may be substituted (mono- or poly-) or unsubstituted. Theheterocyclyl group may be a monocyclic, bicyclic, or tricyclic ringsystem and the rings may be, for example, fused or linked by a singlebond or a linking group such as a methylene or other alkylene group.Nitrogen, carbon or sulfur atoms present in the heterocyclyl radical maybe optionally oxidized and the nitrogen atom may be optionallyquaternized. The heterocyclyl radical may be unsaturated or partially orfully saturated. The heterocyclyl radical may be aliphatic or aromatic.In one embodiment, the heterocyclyl is aliphatic (also known asheteroalicyclyl) and is a 3 to 10 membered ring system where the atomsof the ring or rings consist of carbon atoms and from 1 to 4, or 1, 2 or3 heteroatoms. In one embodiment, the heterocyclyl group is a 6 to 10membered ring system where the atoms of the ring or rings consist ofcarbon atoms and from 1 to 4 heteroatoms and where the ring systemoptionally contains one or two double bonds. In one embodiment, theheterocyclyl is aromatic (also known as heteroaryl) and is a 6 to 10membered ring system where the atoms of the ring or rings consist ofcarbon atoms and from 1 to 4, or 1, 2 or 3 heteroatoms. The greatestpreference is for the term heterocyclyl to refer to a ring of 5 or 6members. Examples of saturated heteroalicyclyl groups are dioxane,piperidine, piperazine, pyrrolidine, morpholine and thiomorpholine.Examples of aromatic heterocyclyl groups are pyridine, pyrrol, furan,thiophene, benzofuran, imidazoline, quinolein, quinoline, pyridazine andnaphthyridine.

The term “aryl group” refers to an aromatic group which has from 6 to30, preferably from 6 to 18, more preferably between 6 and 10, yet evenmore preferably 6 or 10 carbon atoms. The aryl group can comprise 1, 2,3 or 4 aromatic rings, which may be linked by a carbon-carbon bond orfused together and includes, for example and not restricted to, phenyl,naphthyl, diphenyl, indenyl, phenanthryl or antranyl among others. Thearyl group may be substituted (mono- or poly-) or unsubstituted.

The term “aralkyl group” refers to an alkyl group substituted by anaromatic group, with from 7 to 24 carbon atoms and including, forexample and not restricted to, —(CH₂)₁₋₆-phenyl, —(CH₂)₁₋₆-(1-naphthyl),—(CH₂)₁₋₆-(2-naphthyl), —(CH₂)₁₋₆-CH(phenyl)₂ and similar.

The term “heteroarylalkyl” refers to an alkyl group substituted by aheteroaryl (also known as aromatic heterocyclic) group as defined above,the alkyl group having from 1 to 6 carbon atoms and the heteroaryl grouphaving from 2 to 24 carbon atoms and from 1 to 3 heteroatoms.Heteroarylalkyl groups include, for example and not restricted to,—(CH₂)₁₋₆-imidazolyl, —(CH₂)₁₋₆-triazolyl, —(CH₂)₁₋₆-thienyl,—(CH₂)₁₋₆-furyl, —(CH₂)₁₋₆-pyrrolidinyl and similar.

As is understood in this technical field, there may be a certain degreeof substitution of the aforementioned groups. In particular, there canbe substitution in any of the groups identified above where it isexplicitly stated. The substituted groups (radicals) referred to aboveare groups (or radicals) which are substituted in one or more positionsavailable by one or more substituents. Preferably substitution is in the1, 2 or 3 positions, more preferably in the 1 or 2 positions, yet evenmore preferably in the 1 position. Suitable substituents include, forexample and not restricted to: C₁-C₄ alkyl; hydroxyl; C₁-C₄ alkoxyl;amino; amino-C₁-C₄alkyl; C₁-C₄ carbonyloxyl; C₁-C₄ oxycarbonyl; halogensuch as fluoride, chlorine, bromine and iodine; cyano; nitro; azide;C₁-C₄ alkylsulfonyl; thiol; C₁-C₄ alkylthio; aryloxy such as phenoxyl;—NR_(b)(C═NR_(b))NR_(b)R_(c); wherein R_(b) and R_(c) are independentlyselected from the group formed by H, C₁-C₄ alkyl, C₂-C₄ alkenyl,alkynyl, C₃-C₁₀ cycloalkyl, C₆-C₁₈ aryl, C₇-C₁₇ aralkyl, heterocyclyl of3-10 members or protective group of the amino group.

As will be understood and, as indicated above, when it is stated hereinthat R is alkyl, alkenyl, alkynyl, alicyclyl, cycloalkyl, cycloalkenyl,cycloalkenyl, heterocyclyl, heterocyclic, heteroarylalkyl, aryl oraralkyl, etc, it is meant that R is such a group. For example, when itis stated R is alkyl, it is mean that R is an alkyl group. As usedherein, the term “comprising”, which is inclusive or open-ended and doesnot exclude additional unrecited elements or method steps, is intendedto encompass as alternative embodiments, the phrases “consistingessentially of” and “consisting of” where “consisting of” excludes anyelement or step not specified and “consisting essentially of” permitsthe inclusion of additional unrecited elements or steps that do notmaterially affect the essential or basic and novel characteristics ofthe composition or method under consideration.

Compounds of the Invention

A first aspect of the invention relates to a compound of formula (I)

R₁-W_(m)-X_(n)-AA₁-AA₂-AA₃-AA₄-AA₅-AA₆-Y_(p)-Z_(q)-R₂   (I),

-   -   or a stereoisomer and/or cosmetically acceptable salt thereof,        wherein:    -   AA₁ is Asp, Glu, Asn, Gln, Ala, Gly or no amino acid;    -   AA₂ is Val, Ile, Leu or Ala;    -   AA₃ is Tyr, Phe, Trp, Lys, Arg or His;    -   AA₄ is Lys, Arg, His, Pro or Val;    -   AA₅ is Asn, Asp, Gin or no amino acid;    -   AA₆ is Thr, Ala, Ser or no amino acid;    -   W, X, Y and Z are each independently any amino acid;    -   m, n, p and q are each independently 0 or 1;    -   m+n+p+q is less than or equal to 2;    -   R₁ is selected from the group consisting of H, a polymer derived        from polyethylene glycol, a non-cyclic aliphatic group,        alicyclyl, heterocyclyl, heteroarylalkyl, aryl, aralkyl and        R₅—CO—, wherein R₅ is selected from the group consisting of H, a        non-cyclic aliphatic group, alicyclyl, aryl, aralkyl,        heterocyclyl and heteroarylalkyl;    -   R₂ is selected from the group consisting of —NR₃R₄, —OR₃, —SR₃,        wherein R₃ and R₄ are independently selected from a group        consisting of H, a polymer derived from polyethylene glycol, a        non-cyclic aliphatic group, alicyclyl, heterocyclyl,        heteroarylalkyl, aryl and aralkyl; and    -   R₁ and R₂ are not amino acids.

Advantageously, compounds of formula (I) have been found to upregulateMBNL1 protein in skin and skin muscle cells.

The compound of formula (I) is a peptide which comprises 3, 4, 5, 6, 7or 8 amino acids linked in a chain. R₁ is bound to the amino terminalend (N-terminal) of the peptide and R₂ is bound to the carboxy-terminalend (C-terminal) of the peptide.

R₁ can be selected from the group consisting of H, a polymer derivedfrom polyethylene glycol with a molecular weight comprised between 200and 35000 Daltons and R₅—CO—, wherein R₅ is selected from the groupconsisting of C₁-C₂₄ alkyl, C₂-C₂₄ alkenyl, C₂-C₂₄ alkynyl, C₃-C₂₄cycloalkyl, C₅-C₂₄ cycloalkenyl, C₈-C₂₄ cycloalkynyl, C₈-C₃₀ aryl,C₇-C₂₄ aralkyl, 3-10 membered heterocyclyl ring, and a heteroarylalkylcontaining from 2 to 24 carbon atoms and from 1 to 3 heteroatoms,wherein the alkyl group has 1 to 6 carbon atoms.

R₁ can be selected from the group consisting of H and R₅—CO—, wherein R₅is selected from the group consisting of C₁-C₁₈ alkyl, C₂-C₂₄ alkenyl,C₃-C₂₄ cycloalkyl or the group consisting of C₁-C₁₆ alkyl, C₂-C₁₈alkenyl, C₃-C₇ cycloalkyl. The R₅—CO— group includes alkanoyl groupssuch as acetyl (CH₃—CO—, which is abbreviated herein as “Ac-”),myristoyl (CH₃—(CH₂)₁₂—CO—, which is abbreviated herein as “Myr-”) andpalmitoyl (CH₃—(CH₂)₁₄—CO—, which is abbreviated herein as “Palm-”).

R₁ can be selected from the group consisting of H and acetyl,tert-butanoyl, prenyl, hexanoyl, 2-methylhexanoyl, cyclohexanecarboxyl,octanoyl, decanoyl, lauroyl, myristoyl, palmitoyl, stearoyl, oleoyl andlinoleoyl.

R₁ can be selected from the group consisting of H and R₅—CO—, wherein R₅is selected from the group consisting of C₁-C₁₆ alkyl or C₂-C₁₈ alkenyl.

R₁ can be selected from the group consisting of H and R₅—CO—, wherein R₅is C₁-C₁₅ alkyl.

R₁ can be selected from the group consisting of H, acetyl and palmitoyl.Particularly, R₁ is H or acetyl.

R₂ can be selected from the group consisting of —NR₃R₄, —OR₃, —SR₃,wherein R₃ and R₄ are independently selected from the group formed by H,a polymer derived from polyethylene glycol, C₁-C₂₄ alkyl, C₂-C₂₄alkenyl, C₂-C₂₄ alkynyl, C₃-C₂₄ cycloalkyl, C₅-C₂₄ cycloalkenyl, C₈-C₂₄cycloalkynyl, C₆-C₃₀ aryl, C₇-C₂₄ aralkyl, 3-10 membered heterocyclylring, and heteroarylalkyl containing from 2 to 24 carbon atoms and from1 to 3 heteroatoms, wherein the alkyl group has 1 to 6 carbon atoms.Optionally, R₃ and R₄ can be joined by a saturated or unsaturatedcarbon-carbon bond, forming a ring with the nitrogen atom.

R₂ can be —NR₃R₄ or —OR₃. R₃ and R₄ can be independently selected fromthe group consisting of H, a polymer derived from polyethylene glycolwith a molecular weight comprised between 200 and 35000 Daltons, methyl,ethyl, hexyl, dodecyl and hexadecyl. Alternatively, R₃ and R₄ can beindependently selected from the group consisting of H and C₁-C₁₆ alkyl.In one embodiment, R₂ is not OR₃ where R₃ is a methyl group, i.e., R₂ isnot OCH₃. In one embodiment R₃ is H and R₄ is selected from the groupformed by H and C₁-C₁₆ alkyl, including methyl, ethyl, hexyl, dodecyland hexadecyl.

R₂ can be selected from the group consisting of —OH, —NH₂ and —NHR₄where R₄ is C₁-C₁₆ alkyl or C₁-C₃ alkyl or C₁-C₂ alkyl.

R₂ can be —OH or —NH₂. Particularly, R₂ is NH₂.

R₁ can be selected from the group consisting of H and R₅—CO—, wherein R₅is selected from the group consisting of C₁-C₁₈ alkyl, C₂-C₂₄ alkenyl,C₃-C₂₄ cycloalkyl; and R₂ can be —NR₃R₄ or —OR₃, wherein R₃ and R₄ areindependently selected from the group consisting of H and C₁-C₁₆ alkyl.In this embodiment, R₃ can be H and R₄ can be selected from the groupformed by H, C₁-C₁₆ alkyl, C₁-C₃ alkyl and C₁-C₂ alkyl; for example, R₂can be selected from the group consisting of —OH and —NH₂.

R₁ can be selected from the group consisting of H and acetyl,tert-butanoyl, prenyl, hexanoyl, 2-methylhexanoyl, cyclohexanecarboxyl,octanoyl, decanoyl, lauroyl, myristoyl, palmitoyl, stearoyl, oleoyl andlinoleoyl; and R₂ can be —NR₃R₄ or —OR₃ wherein R₃ and R₄ areindependently selected from the group consisting of H and C₁-C₁₆ alkyl.In this embodiment, R₃ can be H and R₄ can selected from the groupformed by H, C₁-C₁₆ alkyl, C₁-C₃ alkyl and C₁-C₂ alkyl; for example, R₂can be selected from the group consisting of —OH and —NH₂.

R₁ can be selected from the group consisting of H and R₅—CO—, wherein R₅is selected from the group consisting of C₁-C₁₆ alkyl or C₂-C₁₈ alkenyl;and R₂ can be —NR₃R₄ or —OR₃, wherein R₃ and R₄ are independentlyselected from the group consisting of H and C₁-C₁₆ alkyl. In thisembodiment R₃ can be H and R₄ can be selected from the group formed byH, C₁-C₁₆ alkyl, C₁-C₃ alkyl and C₁-C₂ alkyl; for example, R₂ can beselected from the group consisting of —OH and —NH₂.

R₁ can be selected from the group consisting of H, acetyl, myristoyl orpalmitoyl; and R₂ can be —NR₃R₄ or —OR₃, wherein R₃ and R₄ areindependently selected from the group consisting of H and C₁-C₁₆ alkyl.In this embodiment R₃ can be H and R₄ can be selected from the groupformed by H, C₁-C₁₆ alkyl, C₁-C₃ alkyl and C₁-C₂ alkyl; for example, R₂can be selected from the group consisting of —OH and —NH₂.

R₁ can be selected from the group consisting of H and R₅—CO—, wherein R₅is C₁-C₁₅ alkyl and R₂ can be —NR₃R₄ or —OR₃, wherein R₃ and R₄ areindependently selected from the group consisting of H and C₁-C₁₆ alkyl.In this embodiment R₃ can be H and R₄ can be selected from the groupformed by H, C₁-C₁₆ alkyl, C₁-C₃ alkyl and C₁-C₂ alkyl; for example, R₂can be selected from the group consisting of —OH and —NH₂.

R₁ can be selected from the group consisting of H, acetyl and palmitoyl,and R₂ can be —NR₃R₄ or —OR₃, wherein R₃ and R₄ are independentlyselected from the group consisting of H and C₁-C₁₆ alkyl. In thisembodiment R₃ can be H and R₄ can be selected from the group formed byH, C₁-C₁₆ alkyl, C₁-C₃ alkyl and C₁-C₂ alkyl; for example, R₂ can beselected from the group consisting of —OH and —NH₂.

R₁ can be selected from the group consisting of H and acetyl, and R₂ canbe —NR₃R₄ or —OR₃, wherein R₃ and R₄ are independently selected from thegroup consisting of H and C₁-C₁₆ alkyl. In this embodiment R₃ can be Hand R₄ can be selected from the group formed by H, C₁-C₁₆ alkyl, C₁-C₃alkyl and C₁-C₂ alkyl; for example, R₂ can be selected from the groupconsisting of —OH and —NH₂.

R₁ can be selected from the group consisting of H and acetyl, and R₂ canbe —NR₃R₄ wherein R₃ and R₄ are independently selected from the groupconsisting of H and C₁-C₁₆ alkyl. In this embodiment R₃ can be H and R₄can be selected from the group formed by H, C₁-C₁₆ alkyl, C₁-C₃ alkyland C₁-C₂ alkyl; for example, R₂ can be selected from the groupconsisting of —NH₂ and —NHR₄ where R₄ is C₁-C₃ alkyl. R₂ can be —NH₂.

R₁ can be H and R₂ can be —NH₂.

R₁ can be selected from the group consisting of a substituted non-cyclicaliphatic group, substituted alicyclyl, substituted heterocyclyl,substituted heteroarylalkyl, substituted aryl, substituted aralkyl andR₅—CO—, wherein R₅ is selected from the group consisting of asubstituted non-cyclic aliphatic group, substituted alicyclyl,substituted aryl, substituted aralkyl, substituted heterocyclyl andsubstituted heteroarylalkyl; and/or R₂ is —NR₃R₄, wherein at least oneof R₃ and R₄ is selected from the group consisting of a substitutednon-cyclic aliphatic group, substituted alicyclyl, substitutedheterocyclyl, substituted heteroarylalkyl, substituted aryl andsubstituted aralkyl, or R₂ is —OR₃, or —SR₃, wherein R₃ is selected fromthe group consisting of a substituted non-cyclic aliphatic group,substituted alicyclyl, substituted heterocyclyl, substitutedheteroarylalkyl, substituted aryl and substituted aralkyl.

In accordance with another particular embodiment the most preferredstructures of the polymer derived from polyethylene glycol are the group(—CH₂—CH₂—O)₁—H in which r is a number comprised between 4 and 795 andthe group

where s is a number comprised between 1 and 125.

The invention provides for a compound of formula (I), wherein at leastone of: R₁ is not H; and R₂ is not OH. That is, the invention providesfor a compound of formula (I) where R₁ is not H and/or R₂ is not OH.

In the compound of formula (I): AA₁ is selected from the groupconsisting of Asp, Glu, Asn, Gln, Ala, Gly and no amino acid; AA₂ isselected from the group consisting of Val, Ile, Leu or Ala; AA₃ isselected from the group consisting of Tyr, Phe, Trp, Lys, Arg and His;AA₄ is selected from the group consisting of Lys, Arg, His, Pro and Val;AA₅ is selected from the group consisting of Asn, Asp, Gln and no aminoacid; and AA₆ is selected from the group consisting of Thr, Ala, Ser andno amino acid. When AA₁, for example, is no amino acid, it means that anamino acid AA₁ is not present in the compound.

The invention provides for a compound of formula (I) which carries theproviso that when there is an amino acid in the AA₅ position, i.e., whenAA₅ is Asn, Asp or Gln, AA₁ is Ala, Gly or no amino acid; AA₂ is Val,Ile or Leu; AA₃ is Lys, Arg or His; AA₄ is Pro or Val; AA₆ is Thr, Ala,Ser or no amino acid; and AA₁ is different from AA₆.

The invention provides for a compound of formula (I) which carries theproviso that when there is no amino acid in the AA₅ position, i.e., AA₅is no amino acid, AA₁ is Asp, Glu, Asn or Gln; AA₂ is Val, Ile, Leu orAla; AA₃ is Tyr, Phe or Trp; AA₄ is Lys, Arg or His; and AA₆ is no aminoacid.

The invention provides for a compound of formula (I) whereby when AA₅ isno amino acid, AA₁ is Asp, Glu, Asn or Gln; AA₂ is Val, Ile, Leu or Ala;AA₃ is Tyr, Phe or Trp; AA₄ is Lys, Arg or His; and AA₆ is no aminoacid. In this embodiment, AA₁ is selected from the group consisting ofAsp, Glu, Asn and Gin; AA₂ is selected from the group consisting of Val,Ile, Leu and Ala; AA₃ is selected from the group consisting of Tyr, Pheand Trp; AA₄ is selected from the group consisting of Lys, Arg and His;AA₅ is no amino acid; and AA₆ is no amino acid. In other words, theinvention provides for a compound of formula (II):

R₁-W_(m)-X_(n)-AA₁-AA₂-AA₃-AA₄-Y_(p)-Z_(q)-R₂   (II),

-   -   or a stereoisomer and/or cosmetically acceptable salt thereof,        wherein:    -   AA₁ is Asp, Glu, Asn or Gin;    -   AA₂ is Val, Ile, Leu or Ala;    -   AA₃ is Tyr, Phe or Trp;    -   AA₄ is Lys, Arg or His;    -   W, X, Y and Z are each independently any amino acid;    -   m, n, p and q are each independently 0 or 1;    -   m+n+p+q is less than or equal to 2;    -   R₁ is selected from the group consisting of H, a polymer derived        from polyethylene glycol, a non-cyclic aliphatic group,        alicyclyl, heterocyclyl, heteroarylalkyl, aryl, aralkyl and        R₅—CO—, wherein R₅ is selected from the group consisting of H, a        non-cyclic aliphatic group, alicyclyl, aryl, aralkyl,        heterocyclyl and heteroarylalkyl;    -   R₂ is selected from the group consisting of —NR₃R₄, —OR₃, —SR₃,        wherein R₃ and R₄ are independently selected from a group        consisting of H, a polymer derived from polyethylene glycol, a        non-cyclic aliphatic group, alicyclyl, heterocyclyl,        heteroarylalkyl, aryl and aralkyl; and    -   R₁ and R₂ are not amino acids.

The compound of formula (II) is a peptide which comprises 4, 5 or 6amino acids linked in a chain. R₁ is bound to the amino terminal end(N-terminal) of the peptide and R₂ is bound to the carboxy-terminal end(C-terminal) of the peptide. R₁ and R₂ are as defined above for thecompound of formula (I).

The invention provides for a compound of formula (II), wherein: AA₁ isselected from the group consisting of Asp, Glu and Asn; AA₂ is selectedfrom the group consisting of Val, Ile, Leu and Ala; AA₃ is selected fromthe group consisting of Tyr, Phe and Trp; and AA₄ is selected from thegroup consisting of Lys, Arg and His. In this embodiment, AA₁ can beselected from Asp and Glu.

The invention provides for a compound of formula (II), wherein: AA₁ isselected from the group consisting of Asp, Glu, Asn and Gln; AA₂ isselected from the group consisting of Val and Ile; AA₃ is selected fromthe group consisting of Tyr, Phe and Trp; and AA₄ is selected from thegroup consisting of Lys, Arg and His. In this embodiment, AA₁ can beselected from Asp, Glu and Asn, or selected from Asp and Glu.

The invention provides for a compound of formula (II), wherein: AA₁ isselected from the group consisting of Asp, Glu, Asn and Gln; AA₂ isselected from the group consisting of Val, Ile, Leu and Ala or the groupconsisting of Val and Ile; AA₃ is selected from the group consisting ofTyr and Phe; and AA₄ is selected from the group consisting of Lys, Argand His. In this embodiment, AA₁ can be selected from Asp, Glu and Asn,or selected from Asp and Glu.

The invention provides for a compound of formula (II), wherein: AA₁ isselected from the group consisting of Asp, Glu, Asn and Gln; AA₂ isselected from the group consisting of Val, Ile, Leu and Ala or the groupconsisting of Val and Ile; AA₃ is selected from the group consisting ofTyr, Phe and Trp or the group consisting of Tyr and Phe; and AA₄ isselected from the group consisting of Lys and Arg. In this embodiment,AA₁ can be selected from Asp, Glu and Asn, or selected from Asp and Glu.

The invention provides for a compound of formula (II), wherein: AA₁ isAsp; AA₂ is Val; AA₃ is Tyr; and AA₄ is Lys.

The invention provides for a compound of formula (I) whereby when AA₅ isAsn, Asp or Gln; AA₁ is Ala, Gly or no amino acid; AA₂ is Val, Ile orLeu; AA₃ is Lys, Arg or His; AA₄ is Pro or Val; AA₆ is Thr, Ala, Ser orno amino acid; and AA₁ is different from AA₆. In this embodiment, AA₁ isselected from the group consisting of Ala, Gly and no amino acid; AA₂ isselected from the group consisting of Val, Ile and Leu; AA₃ is selectedfrom the group consisting of Lys, Arg and His; AA₄ is selected from thegroup consisting of Pro and Val; AA₅ is selected from the groupconsisting of Asn, Asp and Gln; and AA₆ is selected from the groupconsisting of Thr, Ala, Ser and no amino acid; and AA₁ is different fromAA₆. Thus, when AA₁ is Ala, AA₆ is selected from the group consisting ofThr, Ser and no amino acid. Also, when AA₁ is no amino acid, i.e., whenan amino acid AA₁ is not present, amino acid AA₆ must be present, i.e.,AA₆ is selected from the group consisting of Thr, Ala and Ser.Similarly, when AA₆ is Ala, AA₁ is selected from the group consisting ofGly and no amino acid. Similarly, when AA₆ is no amino acid, i.e., whenan amino acid AA₆ is not present, AA₁ is selected from the groupconsisting of Ala and Gly.

Thus, the invention provides for a compound of formula (III):

R₁-W_(m)-X_(n)-AA₁-AA₂-AA₃-AA₄-AA₅-AA₆-Y_(p)-Z_(q)-R₂   (III),

-   -   or a stereoisomer and/or cosmetically acceptable salt thereof,        wherein:    -   AA₁ is Ala, Gly or no amino acid;    -   AA₂ is Val, Ile or Leu;    -   AA₃ is Lys, Arg or His;    -   AA₄ is Pro or Val;    -   AA₅ is Asn, Asp or Gin;    -   AA₆ is Thr, Ala, Ser or no amino acid;    -   AA₁ is different from AA₆;    -   W, X, Y and Z are each independently any amino acid;    -   m, n, p and q are each independently 0 or 1;    -   m+n+p+q is less than or equal to 2;    -   R₁ is selected from the group consisting of H, a polymer derived        from polyethylene glycol, a non-cyclic aliphatic group,        alicyclyl, heterocyclyl, heteroarylalkyl, aryl, aralkyl and        R₅—CO—, wherein R₅ is selected from the group consisting of H, a        non-cyclic aliphatic group, alicyclyl, aryl, aralkyl,        heterocyclyl and heteroarylalkyl;    -   R₂ is selected from the group consisting of —NR₃R₄, —OR₃, —SR₃,        wherein R₃ and R₄ are independently selected from a group        consisting of H, a polymer derived from polyethylene glycol, a        non-cyclic aliphatic group, alicyclyl, heterocyclyl,        heteroarylalkyl, aryl and aralkyl; and    -   R₁ and R₂ are not amino acids.

The compound of formula (III) is a peptide which comprises 5, 6 or 7amino acids linked in a chain. R₁ is bound to the amino terminal end(N-terminal) of the peptide and R₂ is bound to the carboxy-terminal end(C-terminal) of the peptide. R₁ and R₂ are as defined above for thecompound of formula (I).

The invention provides for a compound of formula (III), wherein: AA₁ isselected from the group consisting of Ala and Gly; AA₂ is selected fromthe group consisting of Val, Ile and Leu; AA₃ is selected from the groupconsisting of Lys, Arg and His; AA₄ is selected from the groupconsisting of Pro and Val; AA₅ is selected from the group consisting ofAsn, Asp and Gin; and AA₆ is selected from the group consisting of Thr,Ala, Ser and no amino acid; and AA₁ is different from AA₆.

The invention provides for a compound of formula (III), wherein: AA₁ isselected from the group consisting of Ala, Gly and no amino acid, or thegroup consisting of Ala and Gly; AA₂ is selected from the groupconsisting of Ile and Leu; AA₃ is selected from the group consisting ofLys, Arg and His; AA₄ is selected from the group consisting of Pro andVal; AA₅ is selected from the group consisting of Asn, Asp and Gln; andAA₆ is selected from the group consisting of Thr, Ala, Ser and no aminoacid; and AA₁ is different from AA₆.

The invention provides for a compound of formula (III), wherein: AA₁ isselected from the group consisting of Ala, Gly and no amino acid, or thegroup consisting of Ala and Gly; AA₂ is selected from the groupconsisting of Val, Ile and Leu; AA₃ is selected from the groupconsisting of Lys and Arg; AA₄ is selected from the group consisting ofPro and Val; AA₅ is selected from the group consisting of Asn, Asp andGln; and AA₆ is selected from the group consisting of Thr, Ala, Ser andno amino acid; and AA₁ is different from AA₆. In this embodiment, AA₂can be Leu or Ile.

The invention provides for a compound of formula (III), wherein: AA₁ isselected from the group consisting of Ala, Gly and no amino acid, or thegroup consisting of Ala and Gly; AA₂ is selected from the groupconsisting of Val, Ile and Leu; AA₃ is selected from the groupconsisting of Lys, Arg and His; AA₄ is selected from the groupconsisting of Pro and Val; AA₅ is selected from the group consisting ofAsn and Asp; and AA₆ is selected from the group consisting of Thr, Ala,Ser and no amino acid; and AA₁ is different from AA₆. In thisembodiment, AA₂ can be selected from the group consisting of Leu andIle; and/or AA₃ can be selected from the group consisting of Lys andArg.

The invention provides for a compound of formula (III), wherein: AA₁ isselected from the group consisting of Ala, Gly and no amino acid, or thegroup consisting of Ala and Gly; AA₂ is selected from the groupconsisting of Val, Ile and Leu; AA₃ is selected from the groupconsisting of Lys, Arg and His; AA₄ is selected from the groupconsisting of Pro and Val; AA₅ is selected from the group consisting ofAsn and Gln; and AA₆ is selected from the group consisting of Thr, Ala,Ser and no amino acid; and AA₁ is different from AA₆. In thisembodiment, AA₂ can be selected from the group consisting of Leu andIle; and/or AA₃ can be selected from the group consisting of Lys andArg.

The invention provides for a compound of formula (III), wherein: AA₁ isselected from the group consisting of Ala, Gly and no amino acid, or thegroup consisting of Ala and Gly; AA₂ is selected from the groupconsisting of Val, Ile and Leu; AA₃ is selected from the groupconsisting of Lys, Arg and His; AA₄ is selected from the groupconsisting of Pro and Val; AA₅ is selected from the group consisting ofAsn, Asp and Gln; and AA₆ is selected from the group consisting of Thr,Ala and Ser; and AA₁ is different from AA₆. In this embodiment, AA₂ canbe selected from the group consisting of Leu and Ile; AA₃ can beselected from the group consisting of Lys and Arg; and/or AA₅ can beselected from the group consisting of Asn and Asp.

The invention provides for a compound of formula (III), wherein: AA₁ isAla; AA₂ is Leu; AA₃ is Lys; AA₄ is Pro; AA₅ is Asn; and AA₆ is Thr.

The compounds of the invention can exclude Pro-Leu-Asp-Val-Tyr-Lys,i.e., the invention provides for a compound of formula (I), (II) or(III) as described above, wherein the compound is notPro-Leu-Asp-Val-Tyr-Lys.

The compounds of the invention, i.e., the compound of formula (I), (II)or (III), can exclude Tyr-Lys-Asp-Val-Tyr-Lys, or the embodiment where mis 1 and W is Tyr; n is 1 and X is Lys; AA₁ is Asp; AA₂ is Val; AA₃ isTyr; AA₄ is Lys; AA₅ is no amino acid; AA₆ is no amino acid; p is 0; qis 0; R₁ is H and R₂ is OH.

The compounds of the invention, i.e., the compound of formula (I), (II)or (III), can exclude Arg-Lys-Asp-Val-Tyr-Lys, or the embodiment where mis 1 and W is Arg; n is 1 and X is Lys; AA₁ is Asp; AA₂ is Val; AA₃ isTyr; AA₄ is Lys; AA₅ is no amino acid; AA₆ is no amino acid; p is 0; qis 0; R₁ is H and R₂ is OH.

The compounds of the invention, i.e., the compound of formula (I), (II)or (III), can exclude Arg-Asn-Asp-Val-Tyr-Lys, or the embodiment where mis 1 and W is Arg; n is 1 and X is Asn; AA₁ is Asp; AA₂ is Val; AA₃ isTyr; AA₄ is Lys AA₅ is no amino acid; AA₆ is no amino acid; p is 0; q is0; R₁ is H and R₂ is OH.

The compounds of the invention, i.e., the compound of formula (I), (II)or (III), can exclude Arg-Asp-Val-Tyr-Lys-Gln-Asn, or the embodimentwhere m is 0; n is 1 and X is Arg; AA₁ is Asp; AA₂ is Val; AA₃ is Tyr;AA₄ is Lys; AA₅ is Gln; AA₆ is no amino acid; p is 1 and Y is Asn; q is0; R₁ is H and R₂ is OH.

The compounds of the invention, i.e., the compound of formula (I), (II)or (III), can exclude Asp-Ala-Tyr-Lys, or the embodiment where m is 0; nis 0; AA₁ is Asp; AA₂ is Val; AA₃ is Tyr; AA₄ is Lys; AA₅ is no aminoacid; AA₆ is no amino acid; p is 0 q is 0; R₁ is H and R₂ is OH.

The compounds of the invention, i.e., the compound of formula (I), (II)or (III), can exclude Asp-Ala-Tyr-Lys, or the embodiment where m is 0; nis 0; AA₁ is Asp; AA₂ is Val; AA₃ is Tyr; AA₄ is Lys; AA₅ is no aminoacid; AA₆ is no amino acid; p is 0 q is 0; R₁ is H and R₂ is OH 0.

The compounds of the invention, i.e., the compound of formula (I), (II)or (III), can exclude Asp-Leu-Lys-Lys, or the embodiment where m is 0; nis 0; AA₁ is Asp; AA₂ is Leu; AA₃ is Lys; AA₄ is Lys; AA₅ is no aminoacid; AA₆ is no amino acid; p is 0 q is 0; R₁ is H and R₂ is OH.

The compounds of the invention, i.e., the compound of formula (I), (II)or (III), can exclude His-Asp-Leu-Lys-Lys-Tyr, or the embodiment where mis 0; n is 1; X is His; AA₁ is Asp; AA₂ is Leu; AA₃ is Lys; AA₄ is Lys;AA₅ is no amino acid; AA₆ is no amino acid; p is 1; Y is Tyr; q is 0; R₁is H and R₂ is OH.

Compounds of the invention include those selected from the group ofamino acid sequences listed in Table 2, in which their sequenceidentifier is detailed, their stereoisomers, and/or their cosmeticallyor pharmaceutically acceptable salts.

TABLE 2 Sequence Identifier Asp-Val-Tyr-Lys SEQ ID NO. 1Ala-Leu-Lys-Pro-Asn-Thr SEQ ID NO. 2 Glu-Val-Tyr-Lys SEQ ID NO. 3Asp-Ile-Tyr-Lys SEQ ID NO. 4 Asp-Val-Phe-Lys SEQ ID NO. 5Asp-Val-Tyr-Arg SEQ ID NO. 6 Asn-Val-Tyr-Lys SEQ ID NO. 7Asp-Leu-Tyr-Lys SEQ ID NO. 8 Ala-Asp-Val-Tyr-Lys SEQ ID NO. 9Asp-Val-Tyr-Lys-Ala SEQ ID NO. 10 Ala-Glu-Val-Tyr-Lys SEQ ID NO. 11Ala-Asp-Val-Tyr-Lys-Ala SEQ ID NO. 12 Ala-Ala-Asp-Val-Tyr-LysSEQ ID NO. 13 Ala-Glu-Val-Tyr-Lys-Ala SEQ ID NO. 14 Glu-Ile-Tyr-LysSEQ ID NO. 15 Ala-Glu-Ile-Tyr-Lys-Ala SEQ ID NO. 16 Glu-Ile-Phe-LysSEQ ID NO. 17 Glu-Ile-Tyr-Arg SEQ ID NO. 18 Glu-Ile-Phe-ArgSEQ ID NO. 19 Gly-Leu-Lys-Pro-Asn-Thr SEQ ID NO. 20Ala-Ile-Lys-Pro-Asn-Thr SEQ ID NO. 21 Ala-Leu-Arg-Pro-Asn-ThrSEQ ID NO. 22 Ala-Leu-Lys-Val-Asn-Thr SEQ ID NO. 23Ala-Leu-Lys-Pro-Asp-Thr SEQ ID NO. 24 Ala-Leu-Lys-Pro-Asn-AlaSEQ ID NO. 25 Ala-Leu-Lys-Pro-Asn-Ser SEQ ID NO. 26Ala-Ala-Leu-Lys-Pro-Asn-Thr SEQ ID NO. 27 Ala-Leu-Lys-Pro-Asn-Thr-AlaSEQ ID NO. 28 Ala-Ala-Leu-Lys-Pro-Asn-Thr-Ala SEQ ID NO. 29Leu-Lys-Pro-Asn-Thr SEQ ID NO. 30 Ala-Leu-Lys-Pro-Asn SEQ ID NO. 31Gly-Ile-Lys-Pro-Asn-Thr SEQ ID NO. 32 Gly-Val-Lys-Pro-Asn-ThrSEQ ID NO. 33 Ala-Ile-Arg-Pro-Asn-Thr SEQ ID NO. 34Ala-Ile-Lys-Pro-Asp-Thr SEQ ID NO. 35 Gly-Val-Arg-Pro-Asn-ThrSEQ ID NO. 36 Ala-Ile-Arg-Pro-Asp-Thr SEQ ID NO. 37Gly-Val-Arg-Pro-Asp-Thr SEQ ID NO. 38 Gly-Leu-Lys-Pro-Asn-Thr-AlaSEQ ID NO. 39 Ala-Leu-Lys-Pro-Gln-Thr SEQ ID NO. 40

Compounds of the invention include each of the sequences of Tables 2 inwhich one of amino acids AA₁ to AA₆ is replaced by a replacement aminoacid, wherein the replacement amino acid is selected from thealternative amino acids listed for the amino acid being replaced informula (I), formula (II) or formula (III) above. The replacement aminoacid is different from the amino acid that is being replaced. Thereplacement amino acid can be no amino acid. Thus the invention providesfor a compound of formula (II) corresponding to SEQ ID NO. 1 in whichone of amino acids AA₁ to AA₄ is replaced by an amino acid, wherein:when Asp (AA₁) is replaced it is replaced by Gly, Asn or Gln; when Val(AA₂) is replaced it is replaced by Ile, Leu or Ala; when Tyr (AA₃) isreplaced it is replaced by Phe or Trp; and when Lys (AA₄) is replaced,it is replaced by Arg or Lys. Further, the invention provides for acompound of formula (III) corresponding to SEQ ID NO. 2 in which one ofamino acids AA₁ to AA₆ is replaced by an amino acid, wherein: when Ala(AA₁) is replaced it is replaced by Gly or no amino acid; when Leu (AA₂)is replaced it is replaced by Ile or Val; when Lys (AA₃) is replaced itis replaced by Arg or His; when Pro (AA₄) is replaced, it is replaced byVal; when Asn (AA₅) is replaced it is replaced by Asp or Gln; and whenThr (AA₆) is replaced it is replaced by Ala, Ser or no amino acid;provided AA₁ is not the same as AA₆.

In the amino acid sequences of Table 2 according to formula (I), formula(II) or formula (III), R₁ and R₂ are H and OH, respectively. Compoundsof the invention include each of the sequences of Table 2 with their N-and C-terminals modified by the other R₁ and R₂ groups, respectively, asdefined herein for formula (I), formula (II) or formula (III). Forexample, compounds of the invention include each of the sequences ofTable 2 in which the N-terminal amino acid residue terminates with R₁ asdefined above for formula (I) where R₁ is not H, and, alternatively oradditionally, where the C-terminal amino acid residue optionallyterminates with R₂ as defined above for formula (I), formula (II) orformula (III), where R₂ is not OH.

Thus, in particular, the invention provides for a compound according toformula (I), (II) or (III), wherein the compound is any of the aminoacid sequences SEQ ID NO. 1 to 39 or 40 and its stereoisomers, and/orits cosmetically acceptable salts, wherein optionally, said sequence hasits N-terminal amino acid modified by R₁ as defined above for formula(I), (II) or (III), where R₁ is not H, and, alternatively oradditionally, said sequence has its C-terminal amino acid modified by R₂as defined above for formula (I), where R₂ is not OH. The amino acidsequence can be chosen from SEQ ID NO. 1 and SEQ ID NO. 3 to SEQ ID NO.19. The amino acid sequence can be chosen from SEQ ID NO. 2 and SEQ IDNO. 20 to SEQ ID NO. 39, or from SEQ ID NO. 2 and SEQ ID NO. 20 to 40.The amino acid sequence can be SEQ ID NO. 1 or SEQ ID NO. 2.

The compounds of this invention can exist as stereoisomers or mixturesof stereoisomers; for example, the amino acids which comprise them canhave the configuration L-, D-, or be racemic independently of eachother. Therefore, it is possible to obtain isomeric mixtures as well asracemic mixtures or diastereomeric mixtures, or pure diastereomers orenantiomers, depending on the number of asymmetric carbons and on whichisomers or isomeric mixtures are present. The preferred structures ofthe compounds of the invention are pure isomers, i.e., enantiomers ordiastereomers. For example, when it is stated that AA₂ can be Arg, it isunderstood that, unless otherwise specified, AA₂ is selected from L-Arg,D-Arg or mixtures of both, racemic or non-racemic. The preparationprocedures described in this document enable the person skilled in theart to obtain each of the stereoisomers of the compound of the inventionby choosing the amino acid with the right configuration.

In the context of this invention, the term “amino acids” includes theamino acids encoded by the genetic code as well as non-encoded aminoacids, whether they are natural or not. Examples of non-encoded aminoacids are, without restriction, citrulline, ornithine, sarcosine,desmosine, norvaline, 4-aminobutyric acid, 2-aminobutyric acid,2-aminoisobutyric acid, 6-aminohexanoyc acid, 1-naphthylalanine,2-naphthylalanine, 2-aminobenzoic acid, 4-aminobenzoic acid,4-chlorophenylalanine, 2,3-diaminopropionic acid, 2,4-diaminobutyricacid, cycloserine, carnitine, cystine, penicillamine, pyroglutamic acid,thienylalanine, hydroxyproline, allo-isoleucine, allo-threonine,isonipecotic acid, isoserine, phenylglycine, statin, β-alanine,norleucine, N-methyl amino acids, α-amino acids and β-amino acids, amongothers, as well as their derivatives. A list of non-natural amino acidscan be found in the article “Unusual amino acids in peptide synthesis”by D. C. Roberts and F. Vellaccio, in The Peptides, Vol. 5 (1983),Chapter VI, Gross E. and Meienhofer J., Eds., Academic Press, New York,USA or in the commercial catalogues of the companies specialized in thefield.

In the context of this invention, when W, X, Y and/or Z are present,i.e., at least one of n, m, p or q is not 0, it is understood that thenature of W, X, Y and/or Z does not hinder the activity of the compoundof the invention, and, instead, contributes to it or has no effect onit. W, X, Y and Z can each be independently selected from the groupconsisting of Ala, Gly, Val and Ile. W, X, Y and Z can each beindependently selected from the group consisting of Ala, Gly and Val. W,X, Y and Z can each be independently Ala or Gly. W, X, Y and Z can eachbe Ala.

Each of m, n, p and q can be 0, i.e., the compound of formula (I) is apeptide which comprises 3, 4, 5 or 6 amino acids (e.g., AA₂-AA₃-AA₄,AA₁-AA₂-AA₃-AA₄, AA₂-AA₃-AA₄-AA₅-AA₆ and AA₁-AA₂-AA₃-AA₄-AA₅-AA₆),linked in a chain. Alternatively, the sum of m, n, p and q can be 1,i.e., the compound of formula (I) is a peptide which comprises 4, 5, 6or 7 amino acids linked in a chain. Alternatively, the sum of m, n, pand q can be 2, i.e., the compound of formula (I) is a peptide whichcomprises 5, 6, 7 or 8 amino acids linked in a chain.

Each of m, n, p and q can be 0, i.e., the compound of formula (II) is apeptide which comprises 4 amino acids, AA₁ to AA₄, linked in a chain.Alternatively, the sum of m, n, p and q can be 1, i.e., the compound offormula (I) is a peptide which comprises 5 amino acids linked in achain. Alternatively, the sum of m, n, p and q can be 2, i.e., thecompound of formula (II) is a peptide which comprises 6 amino acidslinked in a chain.

Each of m, n, p and q can be 0, i.e., the compound of formula (III) is apeptide which comprises 5 or 6 amino acids, AA₁ to AA₅, AA₂ to AA₆ orAA₁ to AA₆, linked in a chain. Alternatively, the sum of m, n, p and qcan be 1, i.e., the compound of formula (III) is a peptide whichcomprises 6 or 7 amino acids linked in a chain. Alternatively, the sumof m, n, p and q can be 2, i.e., the compound of formula (III) is apeptide which comprises 7 or 8 amino acids linked in a chain.

In particular, the compound of the invention can be selected from thegroup of compounds listed in Table 3, their stereoisomers, and/or theircosmetically acceptable salts.

TABLE 3 Compound Identifier Ac-Asp-Val-Tyr-Lys-NH₂ PEP1H-Ala-Leu-Lys-Pro-Asn-Thr-NH₂ PEP2 Palm-Asp-Val-Tyr-Lys-NH₂ PEP3Ac-Asp-Val-Tyr-Lys-OH PEP4 H-Asp-Val-Tyr-Lys-NH₂ PEP5Palm-Asp-Val-Tyr-Lys-OH PEP6 Ac-Glu-Val-Tyr-Lys-NH₂ PEP7Ac-Asp-Ile-Tyr-Lys-NH₂ PEP8 Ac-Asp-Val-Phe-Lys-NH₂ PEP9Ac-Asp-Val-Tyr-Arg-NH₂ PEP10 Ac-Asn-Val-Tyr-Lys-NH₂ PEP11Ac-Asp-Leu-Tyr-Lys-NH₂ PEP12 Palm-Glu-Val-Tyr-Lys-NH₂ PEP13Ac-Ala-Asp-Val-Tyr-Lys-NH₂ PEP14 Ac-Asp-Val-Tyr-Lys-Ala-NH₂ PEP15Ac-Ala-Glu-Val-Tyr-Lys-NH₂ PEP16 Ac-Ala-Asp-Val-Tyr-Lys-Ala-NH₂ PEP17Ac-Ala-Ala-Asp-Val-Tyr-Lys-NH₂ PEP18 Ac-Ala-Glu-Val-Tyr-Lys-Ala-NH₂PEP19 Ac-Glu-Ile-Tyr-Lys-NH₂ PEP20 Ac-Ala-Glu-IIe-Tyr-Lys-Ala-NH₂ PEP21Ac-Glu-Ile-Phe-Lys-NH₂ PEP22 Ac-Glu-Ile-Tyr-Arg-NH₂ PEP23Ac-Glu-Ile-Phe-Arg-NH₂ PEP24 Palm-Ala-Leu-Lys-Pro-Asn-Thr-NH₂ PEP25Ac-Ala-Leu-Lys-Pro-Asn-Thr-NH₂ PEP26 Ac-Ala-Leu-Lys-Pro-Asn-Thr-OH PEP27H-Gly-Leu-Lys-Pro-Asn-Thr-NH₂ PEP28 H-Ala-Ile-Lys-Pro-Asn-Thr-NH₂ PEP29H-Ala-Leu-Arg-Pro-Asn-Thr-NH₂ PEP30 H-Ala-Leu-Lys-Val-Asn-Thr-NH₂ PEP31H-Ala-Leu-Lys-Pro-Asp-Thr-NH₂ PEP32 H-Ala-Leu-Lys-Pro-Asn-Ala-NH₂ PEP33H-Ala-Leu-Lys-Pro-Asn-ser-NH₂ PEP34 H-Ala-Ala-Leu-Lys-Pro-Asn-Thr-NH₂PEP35 H-Ala-Leu-Lys-Pro-Asn-Thr-Ala-NH₂ PEP36H-Ala-Ala-Leu-Lys-Pro-Asn-Thr-Ala-NH₂ PEP37Ac-Ala-Ala-Leu-Lys-Pro-Asn-Thr-NH₂ PEP38Pal-Ala-Leu-Lys-Pro-Asn-Thr-Ala-NH₂ PEP39 H-Leu-Lys-Pro-Asn-Thr-NH₂PEP40 H-Ala-Leu-Lys-Pro-Asn-NH₂ PEP41 H-Gly-Ile-Lys-Pro-Asn-Thr-NH₂PEP42 H-Gly-Val-Lys-Pro-Asn-Thr-NH₂ PEP43 H-Ala-Ile-Arg-Pro-Asn-Thr-NH₂PEP44 H-Ala-Ile-Lys-Pro-Asp-Thr-NH₂ PEP45 H-Gly-Val-Arg-Pro-Asn-Thr-NH₂PEP46 H-Ala-Ile-Arg-Pro-Asp-Thr-NH₂ PEP47 H-Gly-Val-Arg-Pro-Asp-Thr-NH₂PEP48 H-Gly-Leu-Lys-Pro-Asn-Thr-Ala-NH₂ PEP49H-Ala-Leu-Lys-Pro-Gln-Thr-NH₂ PEP50

Compounds of the invention include each of the compounds of Table 3 inwhich one of amino acids AA₁ to AA₆ is replaced by a replacement aminoacid, wherein the replacement amino acid is selected from thealternative amino acids listed for the amino acid being replaced informula (I), formula (II) or formula (III) above. The replacement aminoacid is different from the amino acid that is being replaced. Thereplacement amino acid can be no amino acid. Thus the invention providesfor a compound of formula (II) corresponding to SEQ ID NO. 1 in whichone of amino acids AA₁ to AA₄ is replaced by an amino acid, wherein:when Asp (AA₁) is replaced it is replaced by Gly, Asn or Gln; when Val(AA₂) is replaced it is replaced by Ile, Leu or Ala; when Tyr (AA₃) isreplaced it is replaced by Phe or Trp; and when Lys (AA₄) is replaced,it is replaced by Arg or Lys. Further, the invention provides for acompound of formula (III) corresponding to SEQ ID NO. 2 in which one ofamino acids AA₁ to AA₆ is replaced by an amino acid, wherein: when Ala(AA₁) is replaced it is replaced by Gly or no amino acid; when Leu (AA₂)is replaced it is replaced by Ile or Val; when Lys (AA₃) is replaced itis replaced by Arg or His; when Pro (AA₄) is replaced, it is replaced byVal; when Asn (AA₅) is replaced it is replaced by Asp or Gln; and whenThr (AA₆) is replaced it is replaced by Ala, Ser or no amino acid;provided AA₁ is not the same as AA₆.

The invention provides for a compound according to formula (I), whereinthe compound is selected from any of PEP1 to PEP49 or from any of PEP 1to PEP50, and its stereoisomers, and/or its cosmetically orpharmaceutically acceptable salts. The compound of the invention can beselected from PEP1 and PEP3 to PEP24. The compound of the invention canbe selected from PEP2 and PEP25 to PEP49 or from PEP2 and PEP25 toPEP50. Particularly, the compound can be selected from PEP1 and PEP2.

The cosmetically or pharmaceutically acceptable salts of the compoundsprovided by the present invention are also found within the field ofthis invention. The term “cosmetically or pharmaceutically acceptablesalt” means a salt recognized for its use in animals, for example, inmammals, and more specifically in human beings, and includes salts usedto form base addition salts, either they are inorganic, for example andnot restricted to, lithium, sodium, potassium, calcium, magnesium,manganese, copper, zinc or aluminium among others, or they are organic,for example and not restricted to, ethylamine, diethylamine,ethylenediamine, ethanolamine, diethanolamine, arginine, lysine,histidine or piperazine among others, or acid addition salts, eitherthey are organic, for example and not restricted to, acetate, citrate,lactate, malonate, maleate, tartrate, fumarate, benzoate, aspartate,glutamate, succinate, oleate, trifluoroacetate, oxalate, pamoate orgluconate among others, or inorganic, for example and not restricted to,chloride, sulfate, borate or carbonate, among others. The nature of thesalt is not critical, provided that it is cosmetically orpharmaceutically acceptable. The cosmetically or pharmaceuticallyacceptable salts of the compounds of the invention can be obtained bythe conventional methods, well known in the prior art [Berge S. M. etal., “Pharmaceutical Salts”, (1977), J. Pharm. Sci., 66, 1-19].

The invention also provides for a combination of the compound of theinvention, its stereoisomers, and/or its cosmetically acceptable salts,in any of the embodiments described above, with: a Botulinum toxin;Ac-Glu-Glu-Met-Gln-Arg-Arg-NH₂ (Ac-[SEQ ID NO. 41]-NH₂; orH-Tyr-D-Ala-Gly-Phe-Leu-OH; or combinations thereof.

Preparation Procedures of the Compounds of the Invention

Synthesis of the compounds of the invention, their stereoisomers,mixtures thereof and/or their cosmetically or pharmaceuticallyacceptable salts can be carried out according to conventional methods,known in the prior art, such as solid phase peptide synthesis methods[Stewart J. M. and Young J. D., “Solid Phase Peptide Synthesis, 2ndedition”, (1984), Pierce Chemical Company, Rockford, Ill.; Bodanzsky M.and Bodanzsky A., “The practice of Peptide Synthesis”, (1994), SpringerVerlag, Berlin; Lloyd-Williams P. et al., “Chemical Approaches to theSynthesis of Peptides and Proteins”, (1997), CRC, Boca Raton, Fla.,USA], synthesis in solution, enzymatic synthesis [Kullmann W. “Proteasesas catalysts for enzymic syntheses of opioid peptides”, (1980), J. Biol.Chem., 255(17), 8234-8238] or any combination thereof. The compounds canalso be obtained by fermentation of a bacterial strain, modified orunmodified by genetic engineering with the objective of producing thedesired sequences, or by controlled hydrolysis of proteins with animalor plant origins, preferably plant, which results in free peptidefragments that contain the desired sequence.

For example, a method of obtaining the compounds of formula (I), theirstereoisomers and mixtures thereof comprises the stages of:

-   -   coupling of an amino acid, with the N-terminal end protected and        the C-terminal end free, with an amino acid with the N-terminal        end free and the C-terminal end protected or bound to a solid        support;    -   elimination of the protective group of the N-terminal end;    -   repetition of the coupling sequence and elimination of the        protective group of the N-terminal end until the desired peptide        sequence is obtained;    -   elimination of the protective group of the C-terminal end or        cleavage of the solid support.

Preferably, the C-terminal end is bound to a solid support and theprocess is carried out in solid phase and, therefore, comprises thecoupling of an amino acid with the N-terminal end protected and theC-terminal end free, with an amino acid with the N-terminal end free andthe C-terminal end bound to a polymeric support; elimination of theprotective group of the N-terminal end; and repetition of this sequenceas many times as is necessary to thus obtain the compound of desiredlength, finally followed by the cleavage of the synthesized compoundfrom the original polymeric support.

The functional groups of the side chains of the amino acids aremaintained conveniently protected with temporary or permanent protectivegroups throughout synthesis, and can be unprotected simultaneously ororthogonally to the process of cleavage of the peptide from thepolymeric support.

Alternatively, solid phase synthesis can be carried out using aconvergent strategy coupling a peptide with the polymeric support orwith a peptide or an amino acid previously bound to the polymericsupport. Convergent synthesis strategies are widely known by personsskilled in the art and are described in Lloyd-Williams P. et al.,“Convergent Solid-Phase Peptide Synthesis”, (1993), Tetrahedron, 49(48),11065-11133.

The process can comprise the additional stages of deprotection of theN-terminal and C-terminal ends and/or cleavage of the peptide from thepolymeric support in an indiscriminate order, using standard proceduresand conditions known in the prior art, after which the functional groupsof these ends can be modified. The optional modification of theN-terminal and C-terminal ends can be carried out with the peptide offormula (I) anchored to the polymeric support or once the peptide hasbeen separated from the polymeric support.

Optionally, R₁ can be introduced by the reaction of the N-terminal endof the compound of the invention with a R₁—X compound through anucleophilic substitution reaction, in the presence of an adequate baseand solvent, wherein the fragments that have the functional groups notinvolved in the N—C bond formation are suitably protected with temporaryor permanent protective groups. R₁ is as defined above and X is aleaving group, for example and not restricted to, the tosyl group, themesyl group and halogen groups among others.

Optionally and/or additionally, the R₂ radicals can be introduced by thereaction of a compound HR₂ with a complementary fragment whichcorresponds to the peptide of formula (I) in which R₂ is —OH in thepresence of an adequate solvent and a base such asN,N-diisopropylethylamine (DIEA) or trimethylamine, or an additive suchas 1-hydroxybenzotriazole (HOBt) or 1-hydroxyazabenzotriazole (HOAt),and a dehydrating agent such as a carbodiimide, a uronium salt, aphosphonium salt or amidinium salt, among others, or by prior formationof an acyl halide with, for example, thionyl chloride, and therebyobtaining a peptide according to the invention of formula (I), whereinthe fragments that have the functional groups not involved in the N—Cbond formation are suitably protected with temporary or permanentprotective groups. Alternatively other R₂ radicals may be introduced bysimultaneous incorporation to the peptide cleavage process from thepolymeric carrier. R₂ is —OR₃, —NR₃R₄ or —SR₃, where R₃ and R₄ are asdefined above.

A person skilled in the art would easily understand that thedeprotection/cleavage steps of the C-terminal and N-terminal ends andtheir subsequent derivatization can be performed in a different order,according to the processes known in the prior art.

The term “protective group” relates to a group which blocks an organicfunctional group and which can be removed in controlled conditions. Theprotective groups, their relative reactivities and the conditions inwhich they remain inert are known to the person skilled in the art.

Examples of representative protective groups for the amino group areamides, such as amide acetate, amide benzoate, amide pivalate;carbamates such as benzyloxycarbonyl (Cbz or Z), 2-chlorobenzyl (CIZ),para-nitrobenzyloxycarbonyl (pNZ), tert-butyloxycarbonyl (Boc),2,2,2-trichloroethyloxycarbonyl (Troc),2-(trimethylsilyl)ethyloxycarbonyl (Teoc), 9-fluorenylmethyloxycarbonyl(Fmoc) or allyloxycarbonyl (Alloc), trityl (Trt), methoxytrityl (Mtt),2,4-dinitrophenyl (Dnp),N-[1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)ethyl (Dde),1-(4,4-dimethyl-2,6-dioxo-cyclohexylidene)-3-methylbutyl (ivDde),1-(1-adamantyl)-1-methylethoxycarbonyl (Adpoc), among others, preferablyBoc or Fmoc.

Examples of representative protective groups for the carboxyl group areesters, such as the tert-butyl ester (tBu), allyl ester (All),triphenylmethyl ester (Trt tester), cyclohexyl ester (cHx), benzyl ester(Bzl), ortho-nitrobenzyl ester, para-nitrobenzyl ester,para-methoxybenzyl ester, trimethylsilylethyl ester, 2-phenylisopropylester, fluorenylmethyl ester (Fm),4-(N-[1-(4,4-dimethyl-2,6-dioxocyclohexylidene)-3-methylbutyl]amino)benzyl ester (Dmab), among others; preferred protective groups of theinvention are the All, tBu, cHex, Bzl and Trt esters.

The side chains of trifunctional amino acids can be protected during thesynthetic process with temporary or permanent protective groupsorthogonal to the protective groups of the N-terminal and C-terminalends.

The hydroxyl group of the tyrosine side chain can be protected with the2-bromobenzyloxycarbonyl group (2-BrZ), tBu, All, Bzl or2,6-dichlorobenzyl (2,6-diCIZ) among others. In a preferred embodiment,the protective group strategy used is the strategy wherein the aminogroups are protected by Boc, the carboxyl groups are protected by Bzl,cHx or All esters and the tyrosine side chain is protected with 2-BrZ orBzl. In another preferred embodiment, the protective group strategy usedis the strategy wherein the amino groups are protected by Fmoc, thecarboxyl groups are protected by tBu, All or Trt esters, the tyrosineside chain is protected by tBu.

The amino group of the tryptophan side chain can be protected, forexample, by the formyl group (For) or Boc. In one embodiment, when theamino group is protected by Fmoc, and the tryptophan side chain can be:unprotected, i.e., the amino acid is incorporated as Fmoc-Trp-OH;protected by Boc, i.e., the amino acid is incorporated asFmoc-Trp(Boc)-OH; or protected by For, i.e., the amino acid isincorporated as Fmoc-Trp(For)-OH. In one embodiment, the amino group isprotected by Boc, and the tryptophan side chain can be protected by For,i.e., the amino acid is incorporated as Boc-Trp(For)-OH.

Examples of these and other protective groups, their introduction andremoval, can be found in the literature [Atherton B. and Sheppard R. C.,“Solid Phase Peptide Synthesis: A practical approach”, (1989), IRLOxford University Press]. The term “protective groups” also includes thepolymeric supports used in solid phase synthesis.

When synthesis takes place totally or partially in solid phase, thepossible solid supports used in the process of the invention involvepolystyrene support, polyethylene glycol grafted to polystyrene andsimilar, for example and not restricted to, p-methylbenzhydrylamineresins (MBHA) [Matsueda G. R. et al., “A p-methylbenzhydrylamine resinfor improved solid-phase synthesis of peptide amides”, (1981), Peptides,2, 45-50], 2-chlorotrityl resins [Barlos K. et al., “Darstellunggeschützter Peptid-Fragmente unter Einsatz substituierterTriphenylmethyl-Harze”, (1989), Tetrahedron Lett., 30, 3943-3946; BarlosK. et al., “Veresterung von partiell geschützten Peptid-Fragmenten mitHarzen. Einsatz von 2-Chlorotritylchlorid zur Synthese von Leu1-GastrinI”, (1989), Tetrahedron Lett., 30, 3947-3951], TentaGel® resins (RappPolymere GmbH), ChemMatrix® resins (Matrix Innovation, Inc) and similar,which may or may not include a labile linker, such as5-(4-aminomethyl-3,5-dimethoxyphenoxy) valeric acid (PAL) [Albericio F.et al., “Preparation and application of the5-(4-(9-fluorenylmethyloxycarbonyl)aminomethyl-3,5-dimethoxy-phenoxy)valeric acid (PAL) handle for thesolid-phase synthesis of C-terminal peptide amides under mildconditions”, (1990), J. Org. Chem., 55, 3730-3743],2-[4-aminomethyl-(2,4-dimethoxyphenyl)] phenoxyacetic acid (AM) [RinkH., “Solid-phase synthesis of protected peptide fragments using atrialkoxy-diphenyl-methylester resin”, (1987), Tetrahedron Lett., 28,3787-3790], [Wang S. S., “p-Alkoxybenzyl Alcohol Resin andp-Alkoxybenzyloxycarbonylhydrazide Resin for Solid Phase Synthesis ofProtected Peptide Fragments”, (1973), J. Am. Chem. Soc., 95, 1328-1333]and similar, which enable simultaneous deprotection and cleavage of thecompound from the polymeric support.

Applications

The present invention is based on the finding that compounds of formula(I) (the compounds of the invention) are useful in the treatment of theskin, hair, nails and/or mucous membranes. In particular, it has beenfound that compounds of the invention can inhibit upregulated theexpression of muscle bind-like1 (MBNL-1) protein in the skin/skeletalmuscle and thus are useful in the prevention or treatment of thesymptoms of skin aging including skin wrinkles, a sagging appearance ofthe skin and a loss of firmness and for treating or preventing facialasymetry. It has been found that compounds of the invention can inhibitnoradrenaline release and increase collagen synthesis in skin. It hasbeen found that compounds of the invention can increase the lipidcontent of adipose cells and thus can cause an increase in the volume ofadipose tissue. These effects further indicate the usefulness of thecompounds of the invention in the prevention or treatment of thesymptoms of skin aging. Thus, the compounds of formula (I) are useful inthe cosmetic, non-therapeutic treatment of the skin, hair, nails and/ormucous membranes.

MBNL1 is a RNA-binding protein which is implicated in thedifferentiation and maintenance of the splicing pattern required for ahealthy muscle function. Several observations have linked MBNL1 loss offunction as a cause of muscle mass loss during the natural muscle agingprocess in healthy people [Malatesta, M. et al. “Muscle blind-like1undergoes ectopic relocation in the nuclei of skeletal muscles inmyotonic dystrophy and sarcopenia”, (2013), European Journal ofHistochemistry, vol. 57(e15), pp. 86-92; Malatesta, M. et al. “RNAtranscription and maturation in skeletal muscle cells are similarlyimpaired in myotonic dystrophy and sarcopenia: the ultrastructuralevidence”, (2014), Frontiers in Aging Neuroscience, vol. 6(196), pp.1-6]. It has also been demonstrated that an increase of MBNL1 protein infibroblast cells activate their trans-differentiation process tomyofibroblast, a cell-type able to release a higher amount ofextracellular matrix proteins, like collagen, elastin and fibronectin.In fact, electrical stimulation is demonstrated to induce myofibroblastappearance and function [Davis, J. et al. “MBNL1-mediated regulation ofdifferentiation RNAs promotes myofibroblast transformation and thefibrotic response”, (2015), Nature communications, vol. 6(10084), pp.1-14; Jennings, J. A., et al. “Regulation of gene expression in responseto continuous low intensity direct current electrical fields”, (2007),Doctoral Thesis, pp-1-208].

It is believed that an increase of MBNL1 protein in the skin/facialmuscles contributes to the slowing down of and/or avoidance of musclemass loss due to the activation of atrophic processes due to muscleaging. Compounds of the invention are particularly effective atupregulating the expression of muscle blind-like1 (MBNL-1), and are thususeful for preventing or alleviating the effects on cosmetic propertiesof the skin associated with loss of muscle mass due to muscle aging.Thus compounds of the invention are especially useful in maintaining orimproving skin firmness, preventing sagging appearance of the skin,and/or reducing facial asymmetry.

Collagen is the most abundant protein in skin connective tissue; itforms a mesh-like structure that helps to support new cells as they growwhile providing needed flexibility. Type I collagen (Collagen I) is theprincipal collagen of skin and is responsible for the strength andresiliency of this tissue. One of well-recognized characteristics ofaging is sagging of the skin. This is due to a number of factorsincluding loss of elasticity and firmness of the skin, the effect ofgravity, the loss of skeletal support of the face, as well as loss ofsubcutaneous adipose tissue support in the face. An increase in collagensynthesis associated with the increase in MBLN1 protein is considered tobe beneficial to the reduction of the above-mentioned symptoms of skinaging.

The inhibition of noradrenaline release is an indication of inhibitionof neuronal exocytosis, similar to that of the Botulinum toxins. In theneuromuscular junctions, the release of neurotransmitters fromperipheral neurons to skeletal muscle allows muscle contraction. Facialmuscles are also subjected to these contractions. These contractions aremore frequent around the eyes and mouth and in the forehead. With age,continuous release of neurotransmitters into neuromuscular junctions anddecrease of elasticity, contributes to the increase of facial wrinklesand permanent expression lines. Therefore, inhibiting noradrenalinerelease is considered to be beneficial to the reduction these symptomsof aging.

Adipose tissue or body fat is a connective tissue comprising cellscalled adipocytes which accumulate lipids. Advantageously, compounds ofthe invention have been found to be effective increasing the lipidcontent in adipose cell and thus are useful in treatments to increase ofthe volume of adipose tissue, prevent and/or alleviate of effects ofadipose tissue loss.

In one aspect, the invention provides the use of the compound of theinvention, a stereoisomer and/or cosmetically acceptable salt thereof,or a cosmetic composition comprising the compound of the invention, astereoisomer and/or a cosmetically acceptable salt thereof, in thecosmetic, non-therapeutic treatment and/or care of the skin, hair, nailsand/or mucous membranes. In particular, the cosmetic, non-therapeutictreatment and/or care is that of the skin. In the context of thisinvention, skin includes the skin of the whole body including the skinof the face (including skin around the eyes), neckline, neck,décolletage, arms, hands, legs, feet, thighs, hips, buttocks, stomachand torso.

The compounds of the invention are useful in the cosmetic,non-therapeutic treatment and/or care of the skin, including: thetreatment and/or prevention of the aging of the skin, the treatmentand/or prevention of skin wrinkles; maintaining and improving skinfirmness; the stimulation of collagen synthesis and/or prevention ofcollagen loss; the treatment and/or prevention of a sagging appearanceof the skin; the reduction and/or prevention of facial asymmetry; theincrease of the volume of adipose tissue; and/or the prevention and/oralleviation of effects of adipose tissue loss.

The compounds of the invention are useful in the cosmetic,non-therapeutic treatment and/or care of the skin, including: thetreatment and/or prevention of the aging of the skin, the treatmentand/or prevention of skin wrinkles; maintaining and improving skinfirmness; the stimulation of collagen synthesis and/or prevention ofcollagen loss; the treatment and/or prevention of a sagging appearanceof the skin; the reduction and/or prevention of facial asymmetry; theincrease of the volume of adipose tissue; the prevention and/oralleviation of effects of adipose tissue loss; and/or the reduction ofskin roughness and/or the improvement of skin smoothness.

The cosmetic, non-therapeutic treatment and/or care of the skin can be:the treatment and/or prevention of skin wrinkles; maintaining andimproving skin firmness; the stimulation of collagen synthesis and/orprevention of collagen loss.

The cosmetic, non-therapeutic treatment and/or care can involve thestimulation of the synthesis of collagen and/or the upregulation ofMBNL-1 and/or the inhibition of noradrenaline. Thus, the cosmetic,non-therapeutic treatment and/or care of the skin, hair, nails and/ormucous membranes can be associated with increasing collagen synthesisand/or upregulating expression of muscle blind-like1 (MBNL-1) and/or thepresence of noradrenaline.

In one embodiment, there is provided the use of the compound of theinvention, a stereoisomer and/or cosmetically acceptable salt thereof,or a cosmetic composition comprising the compound of the invention, astereoisomer and/or cosmetically acceptable salt thereof, for thetreatment and/or prevention of the aging of the skin. The treatmentand/or prevention is skin aging includes the alleviation and/or theprevention of symptoms of skin aging. The symptoms of skin aging includethe appearance of wrinkles and the loss of skin biomechanical propertiessuch as firmness. The loss of firmness can be due to the reduction incollagen production in the skin or the loss of muscle tone (muscle mass)with age. Particularly, the loss of muscle tone refers to cutaneousmuscles, more particularly to cutaneous facial muscles.

In one embodiment, there is provided the use of the compound of theinvention, a stereoisomer and/or cosmetically acceptable salt thereof,or a cosmetic composition comprising the compound of the invention, astereoisomer and/or cosmetically acceptable salt thereof, for thetreatment and/or prevention of skin wrinkles. Skin wrinkles includeexpression wrinkles, also commonly referred as expression lines.

In one embodiment, there is provided the use of the compound of theinvention, a stereoisomer and/or cosmetically acceptable salt thereof ora cosmetic composition comprising the compound of the invention, astereoisomer and/or cosmetically acceptable salt thereof, formaintaining and/or improving skin firmness.

In one embodiment, there is provided the use of the compound of theinvention, a stereoisomer and/or cosmetically acceptable salt thereof,or a cosmetic composition comprising the compound of the invention, astereoisomer and/or cosmetically acceptable salt thereof, for thestimulation of collagen synthesis and/or prevention of collagen loss.

In one embodiment, there is provided the use of the compound of theinvention, a stereoisomer and/or cosmetically acceptable salt thereof,or a cosmetic composition comprising the compound of the invention, astereoisomer and/or cosmetically acceptable salt thereof, for thetreatment and/or prevention of a sagging appearance of the skin. Saggingappearance can be caused by loss of muscle tone (muscle mass),particularly cutaneous muscle tone, more particularly facial muscles.

In one embodiment, there is provided the use of the compound of theinvention, a stereoisomer and/or cosmetically acceptable salt thereof,or a cosmetic composition comprising the compound of the invention, astereoisomer and/or cosmetically acceptable salt thereof, for thereduction and/or prevention of facial assymmetry.

In one embodiment, there is provided the use of the compound of theinvention, a stereoisomer and/or cosmetically acceptable salt thereof,or a cosmetic composition comprising the compound of the invention, astereoisomer and/or cosmetically acceptable salt thereof, for increasingthe volume of adipose tissue; and/or prevention and/or alleviation ofadipose tissue loss. Particularly, the adipose tissue is subcutaneousadipose tissue, more particularly of the subcutaneous adipose tissue ofthe face, hands and lower part of the neck. The compound of theinvention, a stereoisomer and/or cosmetically acceptable salt thereof,or a cosmetic composition comprising the compound of the invention, astereoisomer and/or cosmetically acceptable salt thereof, can reduce theadquisition of a senescence-associated secretory phenotype (SASP).

In one embodiment, there is provided the use of the compound of theinvention, a stereoisomer and/or cosmetically acceptable salt thereof,or a cosmetic composition comprising the compound of the invention, astereoisomer and/or cosmetically acceptable salt thereof, for thereduction of skin roughness and/or improvement of skin smoothness.

The invention extends to the use of a combination of the compound of theinvention with micro-current electrical neuromuscular stimulation (MENS)treatment in the treatment and/or care of the skin, hair, nails and/ormucous membranes as described above in relation to the applications(uses) of the compounds of the invention. The MENS treatment is acosmetic, non-therapeutic treatment of the skin, hair, nails and/ormucous membrane. For example, MENS treatment typically employs directcurrent (as opposed to alternating) in the range of less of 1 mA, e.g.,300-500 μA, which current may be, optionally, pulsed at a frequency of0.1 to 680 Hz.

The invention also extends to the use of a combination of the compoundof the invention with a Botulinum toxin and/orAc-Glu-Glu-Met-Gln-Arg-Arg-NH₂, in the treatment and/or care of theskin, hair, nails and/or mucous membranes as described above in relationto the applications (uses) of the compounds of the invention.Ac-Glu-Glu-Met-Gln-Arg-Arg-NH₂ is commercialized as Argireline® peptideby Lipotec SAU (Lubrizol) and is known to imitate the cosmetic effectsof Botulinum toxins on the skin in that it inhibits neuronal exocytosis.

In another aspect, the invention provides a method of treatment and/orcare of the skin, hair, nails and/or mucous membranes of a subjectcomprising administering a compound of the invention, a stereoisomerand/or cosmetically or pharmaceutically acceptable salt thereof or acomposition comprising the compound of the invention, a stereoisomerand/or a cosmetically or pharmaceutically acceptable salt thereof, tothe subject. In particular, the invention provides a cosmetic,non-therapeutic method of treatment and/or care of the skin, hair, nailsand/or mucous membranes in a subject comprising administering acosmetically effective amount of a compound of the invention, astereoisomer and/or cosmetically acceptable salt thereof or a cosmeticcomposition comprising a cosmetically effective amount of the compoundof the invention, a stereoisomer and/or a cosmetically acceptable saltthereof, to the subject. The method can be for the treatment and/or careof the skin, hair, nails and/or mucous membranes as described above inrelation to the applications (uses) of the compounds and compositions ofthe invention. In particular, the cosmetic, non-therapeutic method oftreatment and/or care is that of the skin. The administration can betopical or, for example, transdermal. In this aspect of the invention,the compound of the invention may be present in a cosmetic compositionsuch as the cosmetic composition as described herein. In one embodiment,the method involves administering the compound or administering thecomposition using microneedles.

The invention extends to a method of treatment and/or care of the skin,hair, nails and/or mucous membranes of a subject comprisingadministering a combination of the compound of the invention, astereoisomer and/or cosmetically or pharmaceutically acceptable saltthereof and administering cosmetic micro-current electricalneuromuscular stimulation (MENS) treatment to the subject. The methodcan be for the treatment and/or care of the skin, hair, nails and/ormucous membranes as described above in relation to the applications(uses) of the compounds of the invention. The MENS treatment is acosmetic, non-therapeutic treatment of the skin, hair, nails and/ormucous membrane and, for example, typically employs direct current (asopposed to alternating) in the range of 300-500 μA. The current may bepulsed at a frequency of 0.1 to 680 Hz. Preferably, this method oftreatment is a skin antiaging treatment. The compound of the inventioncan be administered simultaneously (at the same time) with the MENStreatment or sequentially with the MENS treatment. The compound of theinvention can be administered before or after the MENS treatment. In anon-limiting example, the method of treatment can involve a cosmetictreatment with MENS followed by administration of the compounds at leastonce a day for a period of time.

The invention also extends to a method of treatment and/or care of theskin, hair, nails and/or mucous membranes of a subject comprisingadministering a combination of the compound of the invention, astereoisomer and/or cosmetically or pharmaceutically acceptable saltthereof with a Botulinum toxin and/or Ac-Glu-Glu-Met-Gln-Arg-Arg-NH₂, tothe subject. The method can be for the treatment and/or care of theskin, hair, nails and/or mucous membranes as described above in relationto the applications (uses) of the compounds of the invention. Forexample, the method of treatment can comprise administering a Botulinumtoxin and a compound of the invention, a stereoisomer and/orcosmetically or pharmaceutically acceptable salt thereof to the subject.For example, the method of treatment can comprise administering:Ac-Glu-Glu-Met-Gln-Arg-Arg-NH₂ and a compound of the invention, astereoisomer and/or cosmetically or pharmaceutically acceptable saltthereof, to the subject. Preferably, this method of treatment is a skinantiaging treatment.

The Botulinum toxin and/or Ac-Glu-Glu-Met-Gln-Arg-Arg-NH₂, and thecompound of the invention can be administered simultaneously (at thesame time) or administered one after the other. When the Botulinum toxinand/or Ac-Glu-Glu-Met-Gln-Arg-Arg-NH₂, and the compound or compositionof the invention are administered at the same time, they can beadministered as a separate dosage forms or as a part of a singlecomposition. When the products are administered in separate dosageforms, the dosage forms can be in the same or different containers.

The above methods of treatment include the cosmetic, non-therapeutictreatment and/or care of the skin, including: the treatment and/orprevention of the aging of the skin, the treatment and/or prevention ofskin wrinkles; maintaining and improving skin firmness; the stimulationof collagen synthesis and/or prevention of collagen loss; the treatmentand/or prevention of a sagging appearance of the skin; the reductionand/or prevention of facial assymmetry; increasing the volume of adiposetissue; and/or prevention and/or alleviation of adipose tissue loss. Inone embodiment, the cosmetic, non-therapeutic method of treatment and/orcare of the skin is a skin antiaging treatment.

The above methods of treatment include the cosmetic, non-therapeutictreatment and/or care of the skin, including: the treatment and/orprevention of the aging of the skin, the treatment and/or prevention ofskin wrinkles; maintaining and improving skin firmness; the stimulationof collagen synthesis and/or prevention of collagen loss; the treatmentand/or prevention of a sagging appearance of the skin; the reductionand/or prevention of facial assymmetry; increasing the volume of adiposetissue; prevention and/or alleviation of adipose tissue loss; and/or thereduction of skin roughness and/or improvement of skin smoothness. Inone embodiment, the cosmetic, non-therapeutic method of treatment and/orcare of the skin is a skin antiaging treatment.

In another aspect, the invention provides a compound of formula (I), astereoisomer and/or a pharmaceutically acceptable salt thereof, or apharmaceutical composition comprising same, for use as a medicament. Inparticular, the invention provides a compound of formula (I), astereoisomer and/or a pharmaceutically acceptable salt thereof, or apharmaceutical composition comprising same, for use in the treatment orprevention of a disease or disorder. In another aspect, the inventionprovides for the use of the compound of formula (I), a stereoisomerand/or a pharmaceutically acceptable salt thereof for the manufacture ofa medicament for the treatment or prevention of a disease or disorder.In another aspect, the invention provides a method of treating orpreventing a disease or disorder in a subject comprising administering atherapeutically effective amount of a compound of formula (I) or apharmaceutical composition comprising same, to the subject.

For the above-described methods of the invention, topical or transdermalapplication can be carried out by iontophoresis, sonophoresis,electroporation, mechanical pressure, osmotic pressure gradient,occlusive cure, microinjections, by needle-free injections by means ofpressure, by microelectric patches, face masks or any combinationthereof.

For the above-described methods of the invention, the frequency ofapplication or administration can vary greatly, depending on the needsof each subject, with a recommendation of an application from once amonth to ten times a day, preferably from once a week to four times aday, more preferably from three times a week to twice a day, even morepreferably once a day. For example, the frequency of the administrationaccording to the method of treatment and/or care of the skin, hair,nails and/or mucous membranes of a subject comprising administering acombination of the compound of the invention, a stereoisomer and/orcosmetically or pharmaceutically acceptable salt thereof with aBotulinum toxin and/or Ac-Glu-Glu-Met-Gln-Arg-Arg-NH₂ to the subject,can vary widely, depending on the need of each subject. In oneembodiment, method of the invention comprises the administration ofBotulinum toxin, followed by the administration of the compound orcompositions of the invention. In a particular embodiment, after theadministration of the Botulinum toxin, the compound or compositions ofthe invention are administered at least once a day for at least oneweek. More particularly, the compound or compositions of the inventionare administered at least once a day until the next administration ofBotulinum toxin.

Compositions of the Invention

The compounds of the invention can be administered for their applicationby any means that causes contact between the compounds and the site ofaction in a subject's body, preferably that of a mammal, preferably ahuman, and in the form of a composition which contains them.

In another aspect, the invention provides a composition comprising acompound according to formula (I), a stereoisomer and/or a cosmeticallyor pharmaceutically acceptable salt thereof.

In particular, the invention provides a cosmetic composition comprisinga compound according to formula (I), a stereoisomer and/or acosmetically acceptable salt thereof, together with at least onecosmetically acceptable excipient or adjuvant. These compositions can beprepared by conventional means known to persons skilled in the art[“Harry's Cosmeticology”, Seventh edition, (1982), Wilkinson J. B.,Moore R. J., ed. Longman House, Essex, GB].

The compounds of this invention have variable solubility in water,according to the nature of their amino acid sequence or any possiblemodifications in the N-terminal and/or C-terminal ends. Therefore, thecompounds of this invention can be incorporated into the compositions byaqueous solution, and those which are not soluble in water can besolubilized in cosmetically or pharmaceutically acceptable conventionalsolvents such as and not restricted to, ethanol, propanol, isopropanol,propylene glycol, glycerin, butylene glycol or polyethylene glycol orany combination thereof.

The cosmetically effective amount of the compounds of the inventionwhich should be administered, as well as their dosage, will depend onnumerous factors, including age, state of the patient, the nature orseverity of the condition, disorder or disease to be treated and/orcared for, the route and frequency of administration and of theparticular nature of the compounds to be used.

The terms “cosmetically effective amount” and “pharmaceuticallyeffective amount” are understood to mean a non-toxic but sufficientamount of the compound or compounds of the invention to provide thedesired effect. The terms “pharmaceutically effective” and“therapeutically effective” are used interchangeably herein. Thecompounds of the invention are used in the cosmetic or pharmaceuticalcompositions of this invention at cosmetically or pharmaceuticallyeffective concentrations to achieve the desired effect; for example, inamounts with respect to the total weight of the composition of: from0.00000001% (in weight) to 20% (in weight); from 0.000001% (in weight)to 15% (in weight), from 0.00001% (in weight) to 10% (in weight); orfrom 0.0001% (in weight) to 5% (in weight).

The compounds of formula (I), their stereoisomers, mixtures thereofand/or their cosmetic or pharmaceutically acceptable salts, can also beincorporated into cosmetic or pharmaceutical delivery systems and/orsustained release systems.

The term “delivery system” relates to a diluent, adjuvant, excipient orcarrier with which the compound of the invention is administered. Thesecosmetic or pharmaceutical carriers can be liquids, such as water, oilsor surfactants, including those of petroleum, animal, plant or syntheticorigin, for example and not restricted to, peanut oil, soybean oil,mineral oil, sesame oil, castor oil, polysorbates, sorbitan esters,ether sulfates, sulfates, betaines, glycosides, maltosides, fattyalcohols, nonoxynols, poloxamers, polyoxyethylenes, polyethyleneglycols, dextrose, glycerol, digitonin and similar. A person skilled inthe art knows the diluents, adjuvants or excipients which can be used inthe different delivery systems in which the compound of the inventioncan be administered.

The term “sustained release” is used in a conventional sense relating toa delivery system of a compound which provides the gradual release ofthis compound during a period of time and preferably, although notnecessarily, with relatively constant compound release levels over aperiod of time.

Examples of delivery or sustained release systems include, withoutrestriction, liposomes, mixed liposomes, oleosomes, niosomes, ethosomes,milliparticles, microparticles, nanoparticles and solid lipidnanoparticles, nanostructured lipid carriers, sponges, cyclodextrins,vesicles, micelles, mixed micelles of surfactants,surfactant-phospholipid mixed micelles, millispheres, microspheres andnanospheres, lipospheres, millicapsules, microcapsules and nanocapsules,as well as in microemulsions and nanoemulsions, which can be added toachieve a greater penetration of the active principle and/or improve itspharmacokinetic and pharmacodynamic properties. Preferred delivery orsustained release systems are liposomes, surfactant-phospholipid mixedmicelles, microemulsions, more preferably water-in-oil microemulsionswith an internal structure of reverse micelle and nanocapsulescontaining microemulsions.

In one embodiment, the invention provides a cosmetic or pharmaceuticalcomposition comprising a compound of formula (I) and a cosmetically orpharmaceutically acceptable carrier selected from the group consistingof creams, emulsions, gels, liposomes, nanoparticles and ointments.

The sustained release systems can be prepared by methods known in theprior art, and the compositions which contain them can be administered,for example, by topical or transdermal administration, includingadhesive patches, non-adhesive patches, occlusive patches andmicroelectric patches, or by systemic administration, for example andnot restricted to, oral or parenteral route, including nasal, rectal orsubcutaneous implantation or injection, or direct implantation orinjection into a specific body part, and preferably should release arelatively constant quantity of the compounds of the invention. Theamount of compound contained in the sustained release system willdepend, for example, on where the composition is to be administered, thekinetics and duration of the release of the compound of the invention,as well as the nature of the condition, disorder and/or disease to betreated and/or cared for.

The compounds of this invention can also be adsorbed on solid organicpolymers or solid mineral supports such as and not restricted to, talc,bentonite, silica, starch or maltodextrin among others.

The compositions which contain the compounds of formula (I), theirstereoisomers, mixtures thereof and/or their cosmetically orpharmaceutically acceptable salts can also be incorporated into fabrics,non-woven fabrics and medical devices which are in direct contact withthe skin, thus releasing the compounds of the invention whether bybiodegradation of the binding system to the fabric, non-woven fabric ormedical device, or by friction between them and the body, due to bodilymoisture, the skin's pH or body temperature. Furthermore, the compoundsof the invention can be incorporated into the fabrics and non-wovenfabrics used to make garments that are in direct contact with the body.

Examples of fabrics, non-woven fabrics, garments, medical devices andmeans for immobilizing the compounds to them, among which are thedelivery systems and/or the sustained release systems described above,can be found in literature and are known in the prior art [Schaab C. K.(1986) HAPPI May 1986; Nelson G., “Application of microencapsulation intextiles”, (2002), Int. J. Pharm., 242(1-2), 55-62; “BiofunctionalTextiles and the Skin” (2006) Curr. Probl. Dermatol. v. 33, Hipler U. C.and Elsner P., eds. S. Karger A G, Basel, Switzerland; Malcolm R. K. etal., “Controlled release of a model antibacterial drug from a novelself-lubricating silicone biomaterial”, (2004), J. Cont. Release, 97(2),313-320]. The preferred fabrics, non-woven fabrics, garments and medicaldevices are bandages, gauzes, t-shirts, socks, tights, underwear,girdles, gloves, diapers, sanitary napkins, dressings, bedspreads,wipes, adhesive patches, non-adhesive patches, occlusive patches,microelectric patches and/or face masks.

The cosmetic or pharmaceutical compositions which contain the compoundsof the invention, their stereoisomers, mixtures thereof and/or theircosmetically or pharmaceutically acceptable salts, can be used indifferent types of compositions for topical or transdermal applicationwhich optionally include cosmetically or pharmaceutically acceptableexcipients necessary for formulating the desired administration form.

The compositions for topical or transdermal application can be producedin any solid, liquid or semisolid formulation, such as and notrestricted to, creams, multiple emulsions such as and not restricted to,oil and/or silicone in water emulsions, water-in-oil and/or siliconeemulsions, water/oil/water or water/silicone/water type emulsions andoil/water/oil or silicone/water/silicone type emulsions, anhydrouscompositions, aqueous dispersions, oils, milks, balsams, foams, lotions,gels, cream gels, hydroalcoholic solutions, hydroglycolic solutions,hydrogels, liniments, sera, soaps, shampoos, conditioners, serums,polysaccharide films, ointments, mousses, pomades, powders, bars,pencils and sprays or aerosols (sprays), including leave-on andrinse-off formulations. These topical or transdermal applicationformulations can be incorporated using techniques known by the personskilled in the art into different types of solid accessories for exampleand not restricted to, bandages, gauzes, t-shirts, socks, tights,underwear, girdles, gloves, diapers, sanitary napkins, dressings,bedspreads, wipes, adhesive patches, non-adhesive patches, occlusivepatches, microelectric patches or face masks, or they can beincorporated into different make-up products such as make-up foundation,such as fluid foundations and compact foundations, make-up removallotions, make-up removal milks, under-eye concealers, eye shadows,lipsticks, lip protectors, lip gloss and powders among others.

The cosmetic or pharmaceutical compositions of the invention may includeagents which increase the percutaneous absorption of the compounds ofthe invention, for example and not restricted to, dimethylsulfoxide,dimethylacetamide, dimethylformamide, surfactants, azone(1-dodecylazacycloheptane-2-one), alcohol, urea, ethoxydiglycol,acetone, propylene glycol or polyethylene glycol, among others.Furthermore, the cosmetic or pharmaceutical compositions of thisinvention can be applied to local areas to be treated by means ofiontophoresis, sonophoresis, electroporation, microelectric patches,mechanical pressure, osmotic pressure gradient, occlusive cure,microinjections or needle-free injections by means of pressure, such asinjections by oxygen pressure, or any combination thereof, to achieve agreater penetration of the peptide of the invention. The applicationarea will be determined by the nature of the condition, disorder and/ordisease to be treated and/or cared for.

Furthermore, the compositions containing the compounds of formula (I),their stereoisomers, mixtures thereof and/or their cosmetically orpharmaceutically acceptable salts can be used in different types offormulations for oral administration, preferably in the form of oralcosmetics or drugs, such as and not restricted to, capsules, includinggelatin capsules, soft capsules, hard capsules, tablets, including sugarcoated tablets, tablets, pills, powders, granules, chewing gum,solutions, suspensions, emulsions, syrups, elixirs, polysaccharidefilms, jellies or gelatins, and any other form known by the personskilled in the art. In a particular embodiment, the compounds of theinvention can be incorporated into any form of functional food orfortified food, such as and not restricted to, dietary bars or compactor non-compact powders. These powders can be dissolved in water, soda,dairy products, soy derivatives or can be incorporated into dietarybars. The compounds of this invention can be formulated with commonexcipients and adjuvants for oral compositions or food supplements, forexample and not restricted to, fat components, aqueous components,humectants, preservatives, texturizing agents, flavors, aromas,antioxidants and colorants common in the food industry.

Cosmetic or pharmaceutical compositions containing the compounds offormula (I), their stereoisomers, mixtures thereof and/or theircosmetically or pharmaceutically acceptable salts can also beadministered, as well as by topical or transdermal route, by any otherappropriate route, such as oral or parenteral route, for which they willinclude the pharmaceutically acceptable excipients necessary for theformulation of the desired administration form. In the context of thisinvention, the term “parenteral” includes nasal, auricular, ophthalmic,rectal, urethral, vaginal, subcutaneous, intradermal route,intravascular injections, such as intravenous, intramuscular,intraocular, intravitreous, intracorneal, intraspinal, intramedullary,intracranial, intracervical, intracerebral, intrameningeal,intraarticular, intrahepatic, intrathoracic, intratracheal, intrathecaland intraperitoneal, and any another similar injection or infusiontechnique. A person skilled in the art knows the different means bywhich the cosmetic or pharmaceutical compositions which contain thecompounds of the invention can be administered.

Among the cosmetically or pharmaceutically acceptable adjuvantscontained in the cosmetic or pharmaceutical compositions described inthis invention are additional ingredients commonly used in cosmetic orpharmaceutical compositions, for example and not restricted toanti-wrinkle agents, botox-like agents and/or anti-aging agents; (ii)firming agents, skin elasticity agents and/or restructuring agents;moisturizing agents; (iv) anti-photoaging agents, and/or blue-lightprotector agents; DNA protecting agents, DNA repair agents, and/or stemcell protecting agents; free radical scavengers and/or anti-glycationagents, detoxifying agents, antioxidant and/or anti-pollution agents;anti-perspirant agents; melanin synthesis stimulating or inhibitingagents; whitening or depigmenting agents; propigmenting agents;self-tanning agents; lipolytic agents or agents stimulating lipolysis,adipogenic agents, etc. Additional examples can be found in CTFAInternational Cosmetic Ingredient Dictionary & Handbook, 12th Edition(2008).

In one embodiment, the invention provides a cosmetic or pharmaceuticalcomposition comprising a compound of formula (I) and a pharmaceuticallyor cosmetically effective amount of an adjuvant selected from the groupconsisting of: (i) anti-wrinkle-agent, botox-like agent and/oranti-aging agent; (ii) firming agent, skin elasticity agent and/orrestructuring agent; (iii) moisturizing agent; (iv) anti-photoagingagent, and/or blue-light protector agent; (v) DNA protecting agent, DNArepair agent, and/or stem cell protecting agent; (vi) free radicalscavengers and/or anti-glycation agent, detoxifying agent, antioxidantand/or anti-pollution agents; and/or combinations thereof.

In a particular embodiment, the anti-wrinkle agent, botox-like agentand/or anti-aging agent is selected from thee group consisting ofMatrixyl® [INCI: Palmitoyl Pentapeptide-4], Matrixyl® 3000® [INCI:Palmitoyl Tetrapeptide-7, Palmitoyl Oligopeptide], Matrixyl® Synthe'6[INCI: Glycerin, Water, Hydroxypropyl Cyclodextrin, PalmitoylTripeptide-38], Matrixyl® Morphomics™ [INCI: Pentylene Glycol, CaprylylGlycol], Essenskin™ [INCI: calcium hydroxymethionine], Renovage [INCI:Teprenone], Dermaxyl® [INCI: Palmitoyl Oligopeptide], Calmosensine™[INCI: Butylene Glycol, Acetyl Dipeptide-1 Cetyl Ester], Volulip™ [INCI:Cetearyl Ethylhexanoate, Sorbitan Isostearate, Portulaca Pilosa Extract,Sucrose Cocoate, Palmitoyl Tripeptide-38], Subliskin™ [INCI:Sinorhizobium Meliloti Ferment, Cetyl Hydroxyethyl Cellulose, Lecithin],Biopeptide™ CL [INCI: Palmitoyl Oligopeptide], Biopeptide EL [INCI:Palmitoyl Oligopeptide], Rigin™ [INCI: Palmitoyl Tetrapeptide-3],Biobustyl [INCI: Glyceryl Polymethacrylate, Rahnella/Soy ProteinFerment, Palmitoyl Oligopeptide], Dynalift™ [INCI: Sodium PolystyreneSulfonate, Sorghum Bicolor Stalk Juice, Glycerin], Idealift™ [INCI:Acetyl Dipeptide-1 Cetyl Ester], Siegesbeckia [INCI: SiegesbeckiaOrientales Extract], Ovaliss™ [INCI: Coco-glucoside, Caprylyl Glycol,Alcohol, Glaucine], Juvinity™ [INCI: Geranylgeranyisopropanol],Prolevis™ [INCI: Hydrolyzed Vegetable Protein], Idealift™ [INCI:Hydroxyethylcellulose, Acetyl Dipeptide-1 cetyl ester], Beautifeye™[INCI: Albizia Julibrissin Bark Extract, Darutoside], Chromocare™ [INCI:Sigesbeckia Orientalis Extract, Rabdosia Rubescens Extract] or Resistem™[INCI proposed: Globularia Cordifolia Ferment] marketed bySederma/Croda. Vialox® [INCI: Pentapeptide-3], Syn®-Ake® [INCI:Dipeptide Diaminobutyroyl Benzylamide Diacetate], Syn®-Coll [INCI:Palmitoyl Tripeptide-5], Phytaluronate™ [INCI: Ceratonia Siliqua (Carob)Gum], Preregen® [INCI: Glycine soja (Soybean) Protein, OxidoReductases], Pepha-Nutrix™ [INCI: Natural Nutrition Factors],Pepha-Tight™ [INCI: Algae Extract, Pullulan], Pentacare-NA™ [INCI:Hydrolyzed Wheat Gluten, Ceratonia Siliqua Gum], Syn®-Tacks [INCI:Glycerin, Palmitoyl Dipeptide-5 Diaminobutyloyl Hydroxythreonine,Palmitoyl Dipeptide-6 Diaminohydroxybutyrate], BeauActive MTP™ [INCI:Hydrolyzed milk protein], Syn®-TC [INCI: TetradecylAminobutyroylvalylaminobutyric Urea Trifluoroacetate, PalmitoylTripeptide-5, Palmitoyl Dipeptide-5 Diaminobutyroyl Hydroxythreonine],Syn®-Hycan [INCI: Tetradecyl Aminobutyroylvalylaminobutyric UreaTrifluoroacetate], Syn®-Glycan [INCI: TetradecylAminobutyroylvalyl-aminobutyric Urea Trifluoroacetate], Regu-Age™ [INCI:Hydrolyzed Rice Bran Protein, Oxido Reductases, Glycine Soja Protein],Pepha-Timp™ [INCI: Human oligopeptide-20], Pepha-Age™ [INCI: DunaliellaSalina Extract], Colhibin™ [INCI: Hydrolyzed Rice Protein], Elhibin[INCI: Glycine Soja Protein, Disodium cocoamphodiacetate] or All-Q™ Plus[INCI: Ubiquinone, Tocopheryl Acetate] marketed by Pentapharm/DSM;Myoxinol™ [INCI: Hydrolyzed Hibiscus esculentus Extract], Myoxinol™ LS9736 [INCI: Hydrolyzed Hibiscus esculentus Extract, Dextrin], Syniorage™[INCI: Acetyl Tetrapeptide-11], Dermican™ [INCI: Acetyl Tetrapeptide-9],DN-AGE® LS [INCI: Cassia alata leaf Extract], Hyalufix GL™ [INCI:Alpinia Galanga Leaf Extract], Neurobiox™ [INCI: Achillea MillefoliumExtract,], Deliner™ [INCI: Zea Mays (Corn) Kernel Extract], Lys′lastineV™ [INCI: Peucedanum Graveolens (Dill) Extract], Extracellium [INCI:Hydrolyzed Potato Protein], Proteasyl TP LS 8657™ [INCI: Pisum SativumExtract], Flavagrum PEG™ [INCI: PEG-6 Isostearate, Hesperetin Laurate],Micromerol™ [INCI: Pyrus Malus Fruit Extract], Extracellium™ [INCI:Hydrolyzed Potato Protein], Marine Filling Spheres [INCI:Pentaerythrityl Tetraisostearate, Silica Dimethyl Silylate, SodiumChondroitin Sulfate, Atelocollagen], Triactigen™ [INCI: Mannitol,Cyclodextrin, Yeast Extract, Disodium Succinate], Eterniskin™ [INCI:Grifola Frondosa Fruiting Body Extract, Maltodextrin], Ascotide™ [INCI:Ascorbyl Phosphate Succinoyl Pentapeptide-12], Hyalurosmooth™ [INCI:Cassia Angustifolia Seed Polysaccharide], Indinyl CA™ [INCI: CassiaAngustifolia Seed Polysaccharide], Arganyl [INCI: Argania Spinosa LeafExtract], Sphingoceryl Veg™ [INCI: Phyto-ceramides], Vit-A-Like [INCI:Vigna Acontifolia Seed Extract], Peptiskin™ [INCI: Arginine/Lysinepolypeptide], Prodejine™ [INCI: Mannitol, Cyclodextrin, Yeast Extract,Disodium Succinate], Aqu′activ™ [INCI: Behenyl Alcohol, Glyceryl Oleate,Cocamide MIPA, Calcium Citrate], Elestan™ [INCI: Glycerin, ManilkaraLeaf Extract], Hibiscin HP™ [INCI: Hibiscus Esculentus Seed Extract],Collalift®18 [INCI: Khaya Senegalensis Bark], Collrepair™ DG [INCI:Hexylene Glycol, Niacin] or Litchiderm™ [INCI: Litchi Chinensis PericarpExtract] marketed by Laboratoires Sérobiologiques/Cognis/BASF;Argireline® [INCI: Acetyl Hexapeptide-8], SNAP-7 [INCI: AcetylHeptapeptide-4], SNAP-8 [INCI: Acetyl Octapeptide-3], Leuphasyl® [INCI:Pentapeptide-18], Inyline® [INCI: Acetyl Hexapeptide-30], Aldenine®[INCI: Hydrolized Wheat Protein, Hydrolized Soy Protein, Tripeptide-1],Preventhelia® [INCI: Diaminopropionoyl Tripeptide-33], Decorinyl® [INCI:Tripeptide-10 Citrulline], Decorinol® [INCI: Tripeptide-9 Citrulline],Trylagen® [INCI: Pseudoalteromonas Ferment Extract, Hydrolyzed WheatProtein, Hydrolyzed Soy Protein, Tripeptide-10 Citrulline,Tripeptide-1], Eyeseryl® [INCI: Acetyl Tetrapeptide-5], Peptide AC29[INCI: Acetyl Tripeptide-30 Citrulline], Relistase® [INCI:Acetylarginyltriptophyl Diphenylglycine], Thermostressine® [INCI: AcetylTetrapeptide-22], Lipochroman™ [INCI: Dimethylmethoxy Chromanol],Chromabright® [INCI: Dimethylmethoxy Chromanyl Palmitate], Antarcticine®[INCI: Pseudoalteromonas Ferment Extract], dGlyage® [INCI: Lysine HCl,Lecithin, Tripeptide-9 Citrulline], Vilastene™ [INCI: Lysine HCl,Lecithin, Tripeptide-10 Citrulline], Hyadisine® [INCI: PseudoalteromonasFerment Extract], Hyanify™ [INCI: Saccharide Isomerate], Diffuporine®[INCI: Acetyl Hexapeptide-37], Silusyne® [INCI: Soybean (Glycine Soja)Oil, Sorbitan Sesquioleate, Isohexadecane, Sodium Hyaluronate,Lauryldimonium Hydroxypropyl Hydrolized Soy Protein, AcetylHexapeptide-39], Adifyline® [INCI: Acetyl Hexapeptide-38], Delisens™[INCI: Acetyl Hexapeptide-46], Telangyn™ [INCI: Acetyl Tetrapeptide-40],Reproage™ peptide [INCI: Acetyl Hexapeptide-8], Cellynkage™ marineingredient [INCI: Saccharide Isomerate], Eyedeline™ marine ingredient[INCI: Plankton Extract], uplevity™ [INCI: Acetyl Tetrapeptide-2],Seacode™ marine ingredient [INCI: Pseudoalteromonas Ferment Extract] orSerilesine® peptide solution [INCI: Hexapeptide-10] marketed byLipotec/Lubrizol; Sirtalice™ [INCI: Bacillus Ferment], Epitensive™[INCI: Nicotiana Benthamiana Hexapeptide-40 SH-Oligopeptide-1],Scelleye™ [INCI: Nicotiana Benthamiana SH-Oligopeptide-2], Seadermium™[INCI: Aqua, Glycerin, Bacillus Ferment], Pauseile [INCI: Aqua,Glycerin, Bacillus Ferment] or Neoclair pro™ [INCI: Aqua, Glycerin,Caprylyl Glycol, Acetyl Tetrapeptide-2] marketed by Lipotrue; Collaxyl®IS [INCI: Hexapeptide-9], Laminixyl IS™ [INCI: Heptapeptide], Orsirtine™GL [INCI: Oryza sativa (Rice) Extract], D′Orientine™ IS [INCI: Phoenixdactylifera (Date) Seed Extract], Phytoquintescine™ [INCI: Einkorn(Triticum monococcum) Extract], Quintescine™ IS [INCI: Dipeptide-4],Peptide Vinci 01™ [INCI: Penta-decapeptide-1], Peptide Vinci 02™ [INCI:Hexapeptide-3], Aquarize IS™ [INCI: Hydrolyzed Rice Extract], Lanablue[INCI: Algae extract], Ederline™ [INCI: Pyrus Malus (Apple) SeedExtract], Dynachondrine™ ISR [INCI:Hydrolized Soy Protein], ProlixirS20™ [INCI: Dimer Tripeptide-43], Phytocohesine™ PSP [INCI: SodiumBeta-Sitosteryl Sulfate, Beta-Sitosterol], Perenityl™ IS [INCI: PyrusCommunis (Pear) Seed Extract], Caspaline 14™ [INCI:Hexapeptide-42],Peptide Q10™ [INCI: Pentapeptide-34 Trifluoroacetate], Survixyl IS™[INCI: Pentapeptide-31], ChroNOgen™ [INCI: Tetrapeptide-26], Elixiance™[INCI: Schinus Molle Extract], Harmoniance™ [INCI: Nelumbo NuciferaFlower Extract], Serenityl™ [INCI: Marsdenia Condurango Bark Extract],Natriance Wrinkle-less™ [INCI: Hydrolyzed Corn Protein], Phytoneomatrix™[INCI: Hydrolyzed Soybean Extract], Prolixir ICE™ [INCI: Hydrolyzed RiceProtein], PhytoRNx Baobab™ [INCI: Hydrolyzed Adansonia DigitataExtract], Natriance™ Renovate Extract [INCI: Hydrolyzed LinseedExtract], Natriance™ Self-Hydrate Extract [INCI: Pisum Sativum Extract],Actopontine YST™ [INCI: Hydrolyzed Yeast Protein] or Telosense™[proposed INCI: Hydrolized Soy Protein, Hydrolized Yeast Protein]marketed by Vincience/ISP/Ashland; BONT-L-Peptide [INCI: PalmitoylHexapeptide-19], TIMP Peptide [INCI: Acetylhexapeptide-20], ECMModuline™ [INCI: Palmitoyl Tripeptide-28], Renaissance™ [INCI:Hydrolyzed Wheat Protein, Palmitoyl Decapeptide-21, Decapeptide-22,Oligopeptide-78, Zinc Palmitoyl Nonapeptide-14] or X50 Antiaging™ [INCI:Lactic Acid/glycolic Acid Copolymer, Polyvinyl Alcohol, Copper PalmitoylHeptapeptide-14, Heptapeptide-15 Palmitate] marketed by InfinitecActivos; EquiStat™ [INCI: Pyrus malus Fruit Extract, Glycine soja SeedExtract], Juvenesce™ [INCI: Ethoxydiglicol and Caprylic Triglyceride,Retinol, Ursolic Acid, Phytonadione, Ilomastat], Ursolisome™ [INCI:Lecithin, Ursolic Acid, Atelocollagen, Xanthan Gum, Sodium chondroitinsulfate], Basaline™ [INCI: Hydrolyzed Malt Extract], Phytokine™ [INCI:Hydrolyzed Soy Protein], marketed by Coletica/Engelhard/BASF; Ameliox™[INCI: Carnosine, Tocopherol, Silybum marianum Fruit Extract] orPhytoCellTec™ Malus Domestica [INCI: Malus domestica Fruit CellCulture], Lipobelle Soyaglicane™ [INCI: Soy Isoflavones], RoyalEpigen™P5 [INCI: Butyrospermum Parkii BUtter, Hydrogenated Lecithin,Maltodextrin, Pentapeptide-48, Phenethyl Alcohol, Ethylhexylglycerin,Glycerin, Water] or DermCom™ [INCI: Crocus Chrysanthus Bulb Extract,Acacia Senegal Gum, Water] marketed by Mibelle Biochemistry; ActiMatrix™[INCI: Peptide based mushroom Extract], Peptamide 6 [INCI:Hexapeptide-11] marketed by Active Organics/Arch; and combinationsthereof.

In another embodiment, the firming agent, skin elasticity agent and/orrestructuring agent is selected, from the group consisting ofArgassential™ [INCI: C10-16 Alkyl Glucoside, Dicaprylyl Ether, Glycerin]or Replexium™ BC [INCI: Dimethyl Isosorbide, Polysorbate 20, Water,Acetyl Tetrapeptide-11, Acetyl Tetrapeptide-9] marketed by BASF;Prolevis™ [INCI: Hydrolyzed Vegetable Protein] or Poretect [INCI:Caprylic/capric Triglyceride, Sorbitan Trioleate, Apium Graveolens SeedExtract, Linum Usitatissimum Seed Extract] marketed by Sederma/Croda;Actifirm™ Ultra Advanced botanical ingredient [INCI: Centella AsiaticaExtract, Rosmarinus Officinalis Leaf Extract, Dipropylene Glycol,Alcohol, Echinacea Angustifolia Leaf Extract] or Actifcol™ Advancedbotanical ingredient [INCI: Water, Glycerin, Sodium Citrate, LentinusEdodes Extract, Potassium Sorbate, Sodium Benzoate, Phytic Acid]marketed by Lipotec/Lubrizol; Densorphin™ [INCI: Vitex Agnus CastusExtract, Aqua, Maltodextrin] or PhytoCellTec™ nunatak® [INCI: Isomalt,Aqua, Saponaria Pumila Callus Culture Extract, Lecithin] marketed byMibelle; and combinations thereof.

In another embodiment, the moisturizing agent is selected from the groupconsisting of Aqua Shuttle™ [INCI: Sorbitol, Laminaria Digitata Extract,Diatomaceous Earth] marketed by Infinitec; Aqua-Osmoline™ [INCI:Ceratonia Siliqua (Carob) Seed Extract] marketed byVincience/ISP/Ashland; Hydralphatine™ Asia [INCI: Hydrogenated StarchHydrolysate, Panthenol, Bambusa Vulgaris Shoot Extract, Nelumbo NuciferaFlower Extract, Nymphaea Alba Root Extract] or Hydraporine™ [INCI:Betaine, Hydrogenated Lecithin, Honey, Pectin] marketed by Lucas MeyerCosmetics/Unipex; PatcH2O™ [INCI: Trehalose, Urea, Serine, GlycerylPolyacrylate, Algin, Sodium Hyaluronate, Pullulan], Aqu'activ™ [INCI:Behenyl Alcohol, Glyceryl Oleate, Cocamide MIPA], Irwinol® [INCI:Octyldodecanol, Irvingia Gabonensis Kernel Butter, HydrogenatedCoco-Glycerides], Lipodermol®) [INCI: Octyldodecanol, ArachidylPropionate, Tocopheryl Acetate, Retinyl Palmitate, Ethyl Linoleate,Ethyl Linolenate] or Seanamin® SU [INCI: Sorbitol, Algae Extract,Chrondrus Crispus (Carrageenan), Fucus Vesiculosus Extract, Algin]marketed by L. Serobiologiques/Cognis/BASF; Snow Algae Powder [INCI:Coenochloris Signiensis Extract] marketed by Mibelle; Hyasol BT™ [INCI:Sodium Hyaluronate], Syn-Up™ [INCI: Benzylsulfonyl D-SerylHomophenylalanine Amidinobenzamide Acetate] or Pentavitin® [INCI:Saccharide Isomerate] marketed by Pentapharm/DSM; Aqualance™ [INCI:Erythritol, Homarine HCl], Hydraprotectol™ [INCI: GlycerylPolymethacrylate, Aleuritic Acid, Yeast Extract (Faex), Glycoprotein],Moist 24™ [INCI: Imperata Cylindrica Root Extract], Optim Hyal™ [INCI:Hydrolyzed Yeast Extract, Cetyl Hydroxyethylcellulose, PolyglucuronicAcid], Osmocide® 4 [INCI: Glycerin, Acrylates/C10-30 Alkyl AcrylateCrosspolymer] or Revidrate™ [INCI: Ethylhexyl Palmitate, SorbitanOleate, Sorbitan Laureate, Myristyl Malate Phosphonic Acid] marketed bySederma/Croda; Xpertmoist® molecular film [INCI: Glycerin,Pseudoalteromonas Ferment Extract, Xanthan Gum, Proline, Alanine,Serine, Ethylhexylglycerin, Caprylyl Glycol] or Actizyme® GL advancedbotanical ingredient [INCI: Glycerin, Mucor miehei extract, Aqua, SodiumCitrate, Potassium Sorbate, Sodium Benzoate, Phytic Acid] marketed byLipotec/Lubrizol; and combinations thereof.

In another embodiment, the anti-photoaging agent, and/or blue-lightprotector agent is selected from the group consisting of AlgaktivGenofix™ CPD [INCI: Plankton Extract, Aqua, Lecithin] marketed byGreenaltech; Blumilight™ Biofunctional [INCI proposed: Water/Aqua (and)Butylene Glycol (and) Theobroma Cacao (Cocoa) Seed Extract] marketed byAshland; Lys′Sun™ [INCI: Hamamelis Virginiana Leaf Extract, Aqua,Pentylene Glycol, Caprylyl Glycol, Xanthan Gum] marketed by BASF;Vitachelox™ [INCI: Vitis Vinifera Seed Extract, Camellia Sinensis LeafExtract, Quercus Robur Wood Extract] marketed by Indena; L-VCG™ [INCI:Ascorbyl Glucoside]marketed by Freshine Bio-technology; Lumicease™ blueingredient [INCI: Glycerin, Aqua, Hydrolyzed Pea Protein, Glucose,Sodium Chloride] marketed by Lipotec/Lubrizol; Lightwaves Defense[JS+M]™ [INCI: Jasminum Sambac Leaf Cell Extract] marketed by Naolys;Blue Oleoactif™ [INCI: Glycine Soja Oil, Polyglyceryl-3 Diisostearate,Oryza Sativa Germ Extract, Oryza Sativa Extract] marketed byOleos-Hallstar; Majestem™ [INCI: Glycerin, Leontopodium Alpinum CallusCulture Extract, Xanthan Gum] or Senestem™ [INCI: Glycerin, PlantagoLanceolata Leaf Extract, Xanthan Gum] marketed by Sederma; Blueshield™[INCI: Glycerin, Capsicum Annuum Fruit Extract, Xanthan Gum] marketed bySolabia; and combinations thereof.

In another embodiment, a DNA protecting agent, DNA repair agent, and/orstem cell protecting agent is selected from the group consisting of;GP4G SP™ [INCI: Aqua, Glycerin, Aretmia Extract], Heliostatine™ [INCI:Aqua, Glycerin, Pisum Sativum Extract], Orsirtine™ [INCI: Aqua,Glycerin, Oryza Sativa Extract], Chronogen™ [INCI: Water, ButyleneGlycol, Tetrapeptide (INCI proposed)], Survixyl IS™ [INCI: Water,Butylene Glycol, Pentapeptide-31] and Chrondricare™ [INCI: Aqua,Butylene Glycol Pentapeptide-28] marketed by Vincience/ISP/Ashland;Lanacityn® [INCI: Glycerin, Aqua, Alteromonas ferment extract,Chysanthellum indicum extract] or Melinoil™ [INCI: Isopropyl Palmitate,Lecithin, Aqua, Acetyl Hexapeptide-1] marketed by AtriumInnovations/Lucas Meyer Cosmetics; Repair Complex™ [INCI: Bifida FermentLysate] marketed by CLR; Phycojuvenine™ [INCI: Laminaria Digitata]marketed by Codif; Unirepair T-43™ [INCI: Butylene Glycol, AcetylTyrosine, Proline, Hydrolyzed Vegetable Protein, Adenosine Triphosphate]marketed by Induchem; Dragosine™ [INCI: Carnosine] marketed by Symrise;DN-Age™ [INCI: Cassia Alata Leaf Extract] marketed by LaboratoriesSerobiologiques/Cognis/BASF; Helioguard™ [INCI: Porphyra Umbilicalisencapsulated into liposomes], PhytoCellTec™ Malus Domestica [INCI:PhytoCellTec Malus Domestica] or PhytoCellTec™ Argan [INCI: ArganiaSpinosa Sprout Cell Extract, Isomalt, Lecithin, Sodium Benzoate, Aqua]marketed by Mibelle Biochemistry; Pepha-Protect™ [INCI: Water MelonExtract] marketed by Pentapharm/DSM; Celligent™ [INCI: Helianthus AnnuusSeed Oil, Ethyl Ferulate, Polyglyceryl-5 Trioleate, RosmarinusOfficinalis Leaf Extract, Aqua, Disodium Uridine Phosphate] or Defensil™[INCI: Octyl Dodecanol, Echium Plantagineum Seed Oil, CardiospermumHalicacabum Extract, Helianthus Annuus Seed Oil Unsaponifiables]marketed by Rahn; Venuceane™ [INCI: Thermus Thermophilus Ferment,Glycerin], UV-Soft [INCI: Yeast Extract], Renovage™ [INCI:Caprylic/Capric Triglyceride, Teprenone], Juvinity™ [INCI:Caprylic/Capric Triglyceride, Geranylgeranylpropanol (proposed)],Phytessence™ Holyherb [INCI: Butylene Glycol, Eriodictyon Californicum(Holyherb) Flower/Leaf/Stem Extract] or Resistem™ [INCI: Glycerin,Globularia Cordifolia Ferment] marketed by Sederma/Croda; Infraguard™[INCI: Caesalpinia Spinosa Fruit Pod Extract, Propylene Glycol, Aqua,Helianthus Annuus Sprout Extract, Sodium Benzoate, Phenoxyethanol]marketed by Mibelle; Heliomoduline™ [INCI: Low molecular weight peptidesfrom cottonseed] or Stem-C-Guard™ [Hydrolyzed Pea] marketed by Silab;and combinations thereof.

In another embodiment, the reactive carbonyl species scavenger, freeradical scavengers and/or anti-glycation agent, detoxifying agent,antioxidant and/or anti-pollution agent is selected, for example and notrestricted to, from the group formed by carnosine and its derivatives;GHK™ [INCI: Tripeptide-1] and its salts and/or derivatives orQuintescine™ IS [INCI: Dipeptide-4] marketed by Vincience/ISP/Ashland;Preregen™ [INCI: Glycine Soja (Soybean) Protein, Oxido Reductases],Edelweiss™ GC [INCI: Leontopodium Alpinum Extract], Lipogard™ [INCI:Squalane, Ubiquinone], Nectapure™ [INCI: Buddleja Davidii Extract,Thymus Vulgaris Extract], Alpaflor™ Nectapure [INCI: Buddleja DavidiiExtract, Thymus Vulgaris Extract, Glycerin, Water] or Dismutin-BTT™[INCI: Highly purified SOD from a natural yeast strain of Saccharomycescerevisiae] marketed by Pentapharm/DSM; Preventhelia® [INCI:Diaminopropionoyl Tripeptide-33], Aldenine® [INCI: Hydrolized WheatProtein, Hydrolized Soy Protein, Tripeptide 1], Lipochroman™ [INCI:Dimethylmethoxy Chromanol], Thermostressine® [INCI: AcetylTetrapeptide-22] Pollushield™ functional ingredient [INCI: DiisopropylAdipate, Lecithin, Acrylic Acid/Acrylamidomethyl Propane Sulfonic AcidCopolymer, Dimethylmethoxy Chromanol, Xanthan Gum] or Bodyfensine®[INCI: Acetyl Dipeptide-3 Aminohexanoate] marketed by Lipotec/Lubrizol;Sunactyl™ [INCI: Mannitol, Pisum Sativum Extract, Histidine HCl,Arginine, Cyclodextrin, Dextrin, Yeast Extract, Acetyl Tyrosine,Pyridoxine HCl, Khaya Senegalensis Bark Extract, Nicotinamide, AdenineDinucleotide, Disodium Succinate, Aspartic Acid], Imidinyl™ [INCI:Tamarindus Indica Seed Polysaccharide], Phystrogene™ [INCI: ButyleneGlycol, Malva Sylvestris (Mallow) Extract, Xanthan Gum] or Purisoft™[INCI: Moringa Pterogysperma Seed Extract] marketed by LaboratoiresSérobiologiques/Cognis/BASF; AquaCacteen™ [INCI: Glycerin, Opuntia FicusIndica Stem Extract, Phenoxyethanol, Aqua], Trimoist™ (KM F) [INCI:Sodium Stearoyl Lactylate, Cetyl alcohol, Olus Vegetable oil, Tocopherylacetate, Glycerin, Glycine soja sterol, Sodium lactate, Sodiumbarboxymethyl betaglucan, Carnosine, Lactic Acid], MelanoBronze™ [INCI:Vitex Agnus Castus Extract (Monk's pepper berries extract(phyto-endorphins)), Acetyl Tyrosine], CM-Glucan™ [INCI: SodiumCarobxymethyl Betaglucan, Phenoxyethanol, SunActin™ [INCI: HelianthusAnnuus (Sunflower) Sprout Extract, Tocopherols, Glycerin, Lecithin,Phenoxyethanol, Aqua], GSP-T skin™ [INCI: Glycerin, Alcohol, Aqua,PEG-40 Hydrogenated Castor Oil, Vitis Vinifera (Grape) Seed Extract] orDetoxophane™ [INCI: Lepidium Sativum Sprout Extract, Lecithin,Phenoxyethanol, Glycerin, Water] marketed by Mibelle Biochemistry;Bacocalmine™ [INCI: PEG-8, Bacopa Monniera Extract, Water (Aqua),Hydroxyethylcellulose], Kombuchka™ [INCI: Saccharomyces/Xylinum BlackTea Ferment, Glycerin, Hydroxyethyl cellulose], Citystem™ [INCI:Glycerin, Marrubium Vulgare Extract] or Prodizia™ [INCI: AlbiziaJulibrissin Extract, Glycerin] marketed by Sederma/Croda; Extramel™ C[INCI: Hydroxypropyltrimonium Maltodextrin Crosspolymer, Cucumis Melo(Melon) Fruit Extract] marketed by Seppic; Defensine™ [INCI: TriticumVulgare Germ Extract], Apolluskin® [INCI: Taraxacum officinale(Dandelion) Extract], Detoxyl® [INCI: Water, Butylene Glycol,Butyrospermum parkii (Shea Butter) Seedcake Extract] or Antiglyskin™[INCI: Aqua, Helianthus Annuus Seed Extract] marketed by Silab; andcombinations thereof.

The compositions of the invention may be for use in any of theapplications or uses discussed above under the heading “Applications”.

In another aspect, the invention provides kit for use in a cosmetic,non-therapeutic method of treatment and/or care of the skin comprising:

(i) a composition comprising Botulinum toxin;

(ii) optionally, a composition comprisingAc-Glu-Glu-Met-Gln-Arg-Arg-NH₂; and

(iii) a cosmetic composition comprising a compound of formula (I), (II)or (III).

The (i) composition comprising Botulinum toxin, (ii) compositioncomprising Ac-Glu-Glu-Met-Gln-Arg-Arg-NH₂, if present, and the (iii)composition comprising the compound of the invention according to thefirst aspect, can be in the same or separate containers. In oneembodiment, the kit can further comprise means to apply the compositionsto the skin. For instance, the kit can comprise means suchs a syringesor microneedles.

The invention is illustrated by the following non-limiting examples.

EXAMPLES General Methods Abbreviations

The abbreviations used for amino acids follow the 1983 IUPAC-IUB JointCommission on Biochemical Nomenclature recommendations outlined in Eur.J. Biochem. (1984) 138:9-37.

(R), resin; 2-CITrt-(R), 2-chlorotrityl resin; Ac, acetyl; AcOH, aceticacid; Ala, alanine; AM, 2-[4-aminomethyl-(2,4-dimethoxyphenyl)]phenoxyacetic acid; Arg, arginine; Asn, asparagine; Asp, aspartic acid;Boc, tert-butyloxycarbonyl; DCM, dichloromethane; DIEA,N,N′-diisopropylethylamine; DIPCDI, N,N′-diisopropylcarbodiimide; DMF,N,N-dimethylformamide; ESI-MS, electrospray ionization massspectrometry; Fmoc, 9-flluorenylmethyloxycarbonyl; Gln, glutamine; Glu,glutamic acid; Gly, Glycine; His, histidine; HOBt,1-hydroxybenzotriazole; HPLC, high performance liquid chromatography;Ile, isoleucine; KOH, potassium hydroxide; Leu, leucine; Lys, lysine;MBHA, p-methylbenzhydrylamine; MeCN, acetonitrile; MeOH, methanol; Met,Methionine; Myr, myristoyl; Palm, palmitoyl; Pbf,2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl; Pro, proline; Ser,serine; tBu, tert-butyl; TFA, trifluoroacetic acid; Thr threonine; Trt,trithyl; Val, valine.

Chemical Synthesis

All synthetic processes are carried out in polypropylene syringes fittedwith porous polyethylene discs. The coupling protocol is carried outfollowing the standard protocols founded in bibliography and thesolvents and soluble reagents are removed by suction. The Fmoc group isremoved with piperidine-DMF (2:8, v/v) (1×1 min, 1×5 min, 5 ml/g resin)[Lloyd-Williams P. et al. (1997) “Chemical Approaches to the Synthesisof Peptides and Proteins” CRC, Boca Raton (Fla., USA)]. Washes betweenstages of deprotection, coupling and, again, deprotection, are carriedout with DMF (3×1 min) each time using 10 ml solvent/g resin. Couplingreactions are performed with 3 ml solvent/g resin. The control of thecouplings is performed by carrying out the ninhydrin test [Kaiser E. etal., Anal. Biochem. (1970), 34: 595-598] or chloranil test [ChristensenT., Acta Chem. Scand., (1979), 33B, 763-766]. The coupling reactions arerepeated as the desired peptide is synthesized. All synthetic reactionsand washes are carried out at 25° C.

It is known by the skilled person that some amino acids are used withtheir functional groups in side chains protected. For instance,non-limiting examples of protecting groups are:

tBu, tert-butyl for amino acid Glu; and

Pbf, 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl for aminoacidArg; and

Trt, trithyl for amino acids Gln.

HPLC chromatographic analysis is carried out with Shimadzu equipment(Kyoto, Japan) using a reversed-phase column thermostatized at 30° C.(50×4.6 mm, Kromasil C18, 3.5 μm, Akzo Nobel, Sweden). The elution iscarried out using a gradient of acetonitrile (+0.07% TFA) in water(+0.1% TFA) at a flow rate of 1.6 mL/min and detection is carried out at220 nm. The electrospray ionization mass spectrometry is carried out ina WATERS Alliance ZQ 2000 detector using a mixture of MeCN:H₂O 4:1(+0.1% TFA) as the mobile phase and a flow rate of 0.3 ml/min.

Example 1

Obtaining Fmoc-W_(m)-X_(n)-AA₁-AA₂-AA₃-AA₄-Y_(p)-Z_(q)-AM-MBHA-(R),wherein AA₁ is L-Asp; AA₂ is L-Val; AA₃ is L-Tyr; AA₄ is L-Lys and n, m,p and q are each 0.

Weights have been normalized. Fmoc-AM-pMBHA resin is treated withpiperidine:DMF according to the described general protocol in order toremove the Fmoc group. 5 equiv of Fmoc-L-Lys(Boc)-OH is incorporatedonto the deprotected resin in the presence of 5.5 equiv of DIPCDI and 5equiv of HOBt using DMF as a solvent for 1 hour.

The resin is then washed as described in general methods and thedeprotection treatment of the Fmoc group is repeated to couple the nextamino acid: 5 equiv of Fmoc-L-Tyr(tBu)-OH; and subsequently 5 equiv ofFmoc-L-Val-OH; 5 equiv of Fmoc-L-Asp(tBu)-OH); are sequentially coupledin the presence of 5 equiv of HOBt and 5.5 equiv of DIPCDI in eachcoupling step.

After the synthesis, the peptidyl resin is washed with DCM (3×1 min).

By following the described method, it is possible to obtain differentsequences changing the desired amino acids to be coupled.

Example 2

ObtainingFmoc-W_(m)-X_(n)-AA₁-AA₂-AA₃-AA₄-AA₅-AA₆-Y_(p)-Z_(q)-AM-MBHA-(R),wherein AA₁ is L-Ala; AA₂ is L-Leu; AA₃ is L-Lys; AA₄ is L-Pro; AA₅ isL-Asn; AA₆ is L-Thr; and n, m, p and q are each 0.

Weights have been normalized. Fmoc-AM-pMBHA resin is treated withpiperidine:DMF according to the described general protocol in order toremove the Fmoc group. 5 equiv of Fmoc-L-Thr(tBu)-OH is incorporatedonto the deprotected resin in the presence of 5.5 equiv of DIPCDI and 5equiv of HOBt using DMF as a solvent for 1 hour.

The resin is then washed as described in the general methods and thedeprotection treatment of the Fmoc group is repeated to couple the nextamino acid: 5 equiv of Fmoc-L-Asn(Trt)-OH; and subsequently 5 equiv ofFmoc-L-Pro-OH; 5 equiv of Fmoc-L-Lys(Boc)-OH; 5 equiv of Fmoc-L-Leu-OH;and finally, 5 equiv of Fmoc-L-Ala-OH are sequentially coupled in thepresence of 5 equiv of HOBt and 5.5 equiv of DIPCDI in each couplingstep.

After the synthesis, the peptidyl resin is washed with DCM (3×1 min).

By following the described method is possible to obtain differentsequences changing the desired amino acids to be coupled.

Example 3

General process for removal of Fmoc N-terminal protective group.

The N-terminal Fmoc group of the peptidyl resins obtained in Examples 1or 2 is deprotected as described in the general methods (20% piperidinein DMF, 1×1 min+1×5 min). The peptidyl resins are washed with DMF (5×1min), DCM (3×1 min), diethyl ether (3×1 min) and dried under vacuum.

Example 4

Process for introducing the R₁ palmitoyl group onto the peptidyl resinsobtained in Example 3.

5 equiv of palmitic acid pre-dissolved in DMF (1 ml) is addedrespectively of each of the peptidyl resins obtained in Example 3, inthe presence of HOBt and DIPCDI. The mixture is allowed to react for 3hours, after which the resin is washed with DMF (3×1 min), DCM (3×1min), diethyl ether (3×1 min) and is dried under vacuum.

Example 5

Process for introducing the R₁ acetyl group onto the peptidyl resinsobtained in Example 3.

Each of the peptidyl resins obtained in Example 3 are treated withacetic anhydride in the presence of DIEA using DMF as a solvent. Themixture is allowed to react for 30 min, after which the resin is washedwith DMF (3×1 min), DCM (3×1 min), diethyl ether (3×1 min) and is driedunder vacuum.

Example 6

Cleavage process from the polymeric support of the peptidyl resinsobtained in Examples 3, 4 and 5.

Each of the dried peptidyl resins obtained in Examples 3, 4 and 5 aretreated with 3 ml of TFA:H₂O (95:5, v/v) for 2 hours at room temperatureunder stirring. Then they are filtered through a polypropylene syringefitted with porous polyethylene discs. The filtrate is collected ontocold diethyl ether, and washed 5 times with diethyl ether. The finalprecipitate is dried under vacuum.

Peptides of general formulasR₁-W_(m)-X_(n)-AA₁-AA₂-AA₃-AA₄-Y_(p)-Z_(q)-OH,R₁-W_(m)-X_(n)-AA₁-AA₂-AA₃-AA₄-NH₂,R₁-W_(m)-X_(n)-AA₁-AA₂-AA₃-AA₄-AA₅-AA₆-Y_(p)-Z_(q)-OH orR₁-W_(m)-X_(n)-AA₁-AA₂-AA₃-AA₄-AA₅-AA₆-Y_(p)-Z_(q)-NH₂, wherein R₁ is H,acetyl or palmitoyl are obtained following this method.

HPLC analyses of the obtained peptides in gradients of MeCN (+0.07% TFA)in H₂O (+0.1% TFA) show a purity exceeding 80% in all cases. Theidentity of the peptides obtained is confirmed by ESI-MS.

Example 7

In vitro quantification of Muscle bind like protein 1 (MBNL1) in humanskeletal muscle cells by Time resolved fluorescence resonance energytransfer.

Aging is linked with a muscle mass loss. A loss of function of Musclebind like protein 1 (MBNL1) is associated with muscle mass loss involvedin the ageing process of facial muscles.

MBNL1 induction by the peptides of the invention is evaluated by a Timeresolved fluorescence resonance energy transfer (TR-FRET) assay. The aimof this study is to investigate the capacity of peptide candidates toincrease MBNL1 in human skeletal muscle cells (hSkMc).

hSkMc (Innoprot) are seeded in 12-well plates at a density of 1.5×10⁴cells/well in Skeletal Muscle Cell Growth Medium (Promocell). After 72hours incubation, medium is removed and replaced with Skeletal MuscleCell Differentiation Medium (Promocell). 48 hours after beginning celldifferentiation, fresh differentiation medium with 0.5 mg/ml of testitems is added. Treatment is continued for 48 hours and non-treatedcells are used as basal control. After 48 hours of treatment, cellmedium is removed and added cell lysis buffer to wells. Immediately,plates are kept at −80° C. in order to improve protein extraction duringthe defrosting process. After 72 hours, cells are lysated by shaking theplates in an orbital rotor at room temperature for 45 minutes. Next,cell lysates are collected and assayed to quantify the level of MBNL1protein and total protein concentration.

MBNL1 protein levels measurement is performed with Human MBNL1 Assay Kit(Cisbio) according to the manufacturer's protocol. Briefly, the kit isused to perform a TR-FRET for MBNL1 quantification. The protein isdetected with the antibodies provided in the kit and quantified by afluorescence measurement. The quantification is carried out by using amicroplate reader (ClarioStar, BMG) set to 665 nm and 620 nm.

Total protein concentration of cell lysate is determined by using PierceBCA Protein Assay Kit™ (Thermo Scientific) according to manufacturer'sprotocol. In brief, after adding Working Reagent to the samples and thestandards, the samples are incubated. Afterwards, color change ismeasured with an absorbance microplate reader (Clariostar™, BMG) at 562nm. The total protein amount is used to normalize the level of MBNL1protein concentration obtained by the TR-FRET test in the samples.

The results demonstrate that peptides PEP1 (Ac-Asp-Val-Tyr-Lys-NH₂) andPEP2 (H-Ala-Leu-Lys-Pro-Asn-Thr-NH₂) of the invention increase MBNL1levels when compared to the basal control (FIG. 1). It is believed thatthe enhancement of MBNL1 protein slows the muscle mass loss duringaging, thus avoiding the appearance of sagging face skin in olderpeople.

Example 8

In vitro quantification of Muscle bind like protein 1 (MBNL1) in humandermal fibroblasts by Immunofluorescence.

An increase of collagen synthesis is considered beneficial to reduceaging signs. Muscle bind like protein 1 (MBNL1) in fibroblast activatesits transdifferentiation to myofibroblast. These cells can release ahigher amount of extracellular matrix proteins such as collagen, elastinor fibronectin preventing wrinkle appearance.

MBNL1 induction by the peptides of the invention is evaluated by anImmunofluorescence assay. The aim of this study is to investigate thecapacity of peptide candidates to increase MBNL1 in human dermalfibroblasts (HDF).

HDF (Cascade) are seeded in 96-well plates at a density of 8×10³cells/well in Fibroblast Growth Medium (Promocell). After 48 hoursincubation, medium is removed and fresh medium with 1, 0.5 and 0.01mg/ml of test items is added. Treatment is continued for 24 hours andnon-treated cells are used as basal control. After 24 hours oftreatment, an immunofluorescence is performed. Cells are fixed 15minutes with 4% Paraformaldehide (Sigma), permeated 15 minutes with 1%Triton X-100 (Sigma) and then blocked with 5% Bovine Serum Albumin(Sigma). Next, primary antibody Anti-MBNL1 Rabbit (Sigma) is added andincubated for 2 hours. After that, secondary antibody Alexa Fluor™ 488goat anti-rabbit IgG (Life Technologies) is added and incubated for 1hour. To stain nuclei, Hoechst (Life Technologies) is added andincubated for 10 minutes. Finally, MBNL1 cell nuclei fluorescenceintensity and nuclei number are measured by Operetta™ (Perkin Elmer).Fluorescence is normalized by cell nuclei and results are representedrespect to basal control. Results are shown in FIG. 2.

The results demonstrate that peptides PEP1 (Ac-Asp-Val-Tyr-Lys-NH₂) andPEP2 (H-Ala-Leu-Lys-Pro-Asn-Thr-NH₂) of the invention increase MBNL1levels when compared to the basal control.

Example 9

In vitro prevention of muscle mass loss induced in human skeletal musclecells by immunofluorescence.

Muscle mass loss is related to facial muscle aging. It has beensuggested that loss of function of Muscle bind like protein 1 (MBNL1) inmuscle cells could be related with muscle mass loss in aging. It hasalso been described in literature that myotube diameter in muscle cellsis an indicator of muscular mass loss when it is under 20 μm.

Myosin heavy chain (MHyC) is used as a morphologic marker ofdifferentiated myotubes allowing the measurement of their diameter, andtherefore knowing their degree of mass loss. Tumor necrosis factor α(TNF-α) has been described in the literature as a muscle mass lossinductor.

Muscle mass loss prevention by the peptides of the invention isevaluated by an immunofluorescence assay. The aim of this study is toinvestigate the capacity of peptide candidates to prevent muscular massloss in presence of TNF-α in human muscular skeletal cells (hSKMC).

hSKMC (Tebu-Bio) are seeded in 96-well plates at a density of 1.5×10⁴cells/well in Skeletal Muscle Cell Growth Medium (Promocell). After 24hours incubation, medium is replaced with Skeletal Muscle CellDifferentiation Medium (Promocell) and cells are differentiated for 6days. After this, fresh differentiation medium with 0.5 mg/ml of testitems and 20 ng/ml of TNFα (Sigma) is added. Treatment is continued for48 hours and non-treated cells are used as basal control and 20 ng/mlTNFα treated cells are used as a muscle mass loss control. After 48hours of treatment, an immunofluorescence is performed. Cells are fixed15 minutes with 4% Paraformaldehide (Sigma), permeated 15 minutes with1% Triton™ X-100 (Sigma) and then blocked with 5% Bovine Serum Albumin(Sigma). Next, primary antibody Anti-MHyC mouse (1:100, Vitro) is addedand incubated for 2 hours. After that, secondary antibody Alexa Fluor™488 goat anti-mouse IgG (1:250, Life Technologies) is added andincubated for 1 hour. Finally, myotube diameter is determined by imagingMHyC staining by Operetta™ (Perkin Elmer). Percentage of mass loss isautomatically calculated with Harmony™ (Perkin Elmer) software byclassifying myotubes according to their diameter using an atrophicthreshold of 20 μm. Results shown in FIG. 4 and are normalized versusTNF-α.

The results demonstrate that peptides PEP1 and PEP2 of the inventionprevent mass loss when compared to TNF-α treatment.

Example 10

In vitro alleviation of the effects of muscle mass loss induced in humanskeletal muscle cells by immunofluorescence.

Muscle mass loss correction by the peptides of the invention isevaluated by an immunofluorescence assay. The aim of this study is toinvestigate the capacity of peptide candidates to correct muscular massloss after treatment with TNF-α in human muscular skeletal cells(hSKMC). Myosin heavy chain (MHyC) is used as a morphologic marker ofdifferentiated myotubes allowing the measurement of their diameter, andtherefore knowing their degree of mass loss. Tumor necrosis factor α(TNF-α) has been described in the literature as a muscle mass lossinductor.

hSKMC (Tebu-Bio) are seeded in 96-well plates at a density of 1.5×10⁴cells/well in Skeletal Muscle Cell Growth Medium (Promocell). After 24hours incubation, medium is replaced with Skeletal Muscle CellDifferentiation Medium (Promocell) and cells are differentiated for 6days. After this, muscular cells mass loss is induced by adding freshdifferentiation medium with 20 ng/ml TNFα (Sigma). Non-TNFα treatedcells are used as basal mass loss control (BC). After 24 hours of massloss induction, the culture medium is replaced with freshdifferentiation medium comprising 0.01 mg/ml of the peptides of theinvention. TNFα treated cells are used as mass loss control (BCN+TNF)and cells non-treated with neither the peptides of the invention itemsnor TNFα are used as basal mass loss control (BC). Treatment is renewed24 hours later. After 24 hours after the second treatment,immunofluorescence is determined. Cells are fixed 15 minutes with 4%Paraformaldehyde (Sigma), permeated 15 minutes with 1% Triton™ X-100(Sigma) and then blocked with 5% Bovine Serum Albumin (Sigma). Next,primary antibody Anti-MHyC mouse (1:100, Vitro) is added and incubatedovernight at 4° C. After that, secondary antibody Alexa Fluor™ 488 goatanti-mouse IgG (1:250, Life Technologies) is added and incubated for 1hour. Finally, myotube diameter is determined by imaging MHyC stainingby Operetta™ (Perkin Elmer). Percentage of mass loss is automaticallycalculated with Harmony™ (Perkin Elmer) software by classifying myotubesaccording to their diameter using a mass loss threshold of 20 μm.Results show in FIG. 4. are normalized versus mass loss control.

The results demonstrate that peptides PEP1 and PEP2 of the inventioncorrect (i.e., reduces) mass loss when compared to basal control treatedwith TNF-α.

Example 11

In vitro study of type I collagen synthesis on human dermal fibroblastsby AlphaLISA.

Collagen induction by the peptides of the invention is evaluated with anAlphaLISA assay. The aim of this study is to investigate the ability ofa product to induce collagen type I synthesis in human dermalfibroblasts isolated from adult skin (HDFa).

HDFa (Promocell) are seeded in 48-well plates at a density of 1×10⁵ inFibroblast Growth Medium supplemented with C-39016 (Promocell). After24-hours incubation, fresh Medium 106 supplemented with Low Serum GrowthSupplement (Gibco) with 0.5 μg/ml of the test items is added. Treatmentis continued for 48 hours and non-treated cells are used as basalcontrol. After 48 hours treatment, cell supernatants are collected.Protease Inhibitor Cocktail (Sigma) is added to each supernatant andthen are kept at -80° C. until they are analysed by AlphaLISA withAlphaLISA COL1A1™ Detection kit (PerkinElmer) following themanufacturer's instructions. Briefly, Donor beads and acceptor beads inthe presence of Collagen type I are close enough to produce aluminescent signal directly proportional to the amount of Collagen TypeI present in each condition tested. The luminescence produced by thisreaction is measured in a microtiter plate reader and type I collagenconcentration is determined using a linear regression of the standardcurve. Results of collagen synthesis versus non-treated cells are shownin FIG. 5.

The results demonstrate that the peptides of the invention boost type Icollagen production respect to basal conditions in HDFa at testedconcentration.

Example 12

Inhibition of noradrenaline release from human neuroblastoma cells.

The aim of this study is to evaluate the efficacy of the peptides of theinvention on the inhibition of neuronal exocytosis by means of measuringthe levels of noradrenaline (NA) release in human neuroblastoma cellline (SH-SY5Y cells) by Enzyme-linked Immunosorbent Assay (ELISA).

SH-SY5Y (ECACC) cells are seeded in 12-well plates at a density of 1×10⁶cells/well. After a 6-day culture, medium is removed from wells andcells are treated for 60 minutes with the peptides of the inventiondissolved in Hank's Balanced Salt Solution (HBSS, Life Technologies) at0.01 and 0.5 mg/ml. Cells treated with HBSS alone are used as a basalcontrol. To mobilize NA vesicles, supernatants are removed and 100 nMTetradecanoylphorbol-13-acetate (TPA, Sigma) is dissolved in thepresence of test items in HBSS or dissolved in HBSS alone in the case ofthe basal control. After this, solutions with TPA are removed and NArelease is induced by the addition of 10 μM Ionomycin (Epica) with 100nM TPA dissolved in the presence of test items in HBSS or dissolved inHBSS alone in the case of the basal control. Afterwards, the medium inthe wells, containing released NA, is collected and centrifuged.Supernatants obtained are used for quantification of NA by ELISA withnoradrenalin ELISA kit (IBL International) following manufacturer'sinstructions. In brief, direct sandwich ELISA is performed with a platepre-coated with an anti-NA antibody. The color obtained after substrateaddition is directly proportional to the amount of NA present in eachcondition tested. Absorbance is read in a microplate absorbance reader(Clariostar, BMG) at 405 nm. The percentage of NA release for eachcondition is calculated respect to basal control. Results of percentageof NA release versus non-treated cells (basal control) are shown in FIG.6.

The results demonstrate that the peptides of the invention inhibit NArelease respect to basal conditions in SH-SY5Y at testedconcentration(s). An increase of exocytosis release in neuromuscularjunction is related with aging and with an increase of facial wrinklesand expression lines. The peptides of the invention reduce exocytosislevels as they reduce NA release in SH-SY5Y.

Example 13

In vitro lipid accumulation in human subcutaneous pre-adipocytes.

The aim of this study is to investigate the capacity of peptidecandidates to induce lipid accumulation in human subcutaneousadipocytes, and therefore prevent adipocytes senescence. Measurement oflipid accumulation in a coculture of young and old adipose cellsindirectly evaluates the inhibition of senescence-associated secretoryphenotype (SASP). A pool of old adipose cells has a higher number ofsenescent cells. When cocultured with young cells, lipid accumulationobserved is below the theoretically expected levels due to senescenceinduction effect of SASP on young adipocytes.

Induction of lipid accumulation by the peptides of the invention isevaluated by lipid fluorescent staining with Adipored® Assay Reagent.Human subcutaneous pre-adipocytes (26-year-old and 60-year-old donors,Cell applications) cells are cocultured in 96-well plates at a densityof 4×10³ cells/well each age in Human Preadipocyte Growth Medium(Sigma). Monoculture of each age are seeded at a density of 8×10³cells/well as age lipid accumulation controls. After 24 hoursincubation, differentiation of pre-adipocytes into adipocytes is inducedby changing medium to fresh Human Preadipocyte Differentiation Medium(Promocell). At the same time, cocultured cells are treated with 0.01mg/ml of test items. Non-treated cocultured cells are used as basalcontrol and monocultured young and old cells as age lipid accumulationcontrols. After 12 days of treatment and differentiation, cells arestained with Adipored® Assay Reagent (Lonza) following themanufacturer's instructions. In brief, the plate is washed withPhosphate Buffer Saline (Sigma) and then Adipored® reagent and Hoechst33342 (Life technologies) are added and incubated for 15 minutes at 37°C. Finally, fluorescence intensity and nuclei number are measured byOperetta™ (Perkin Elmer). Fluorescence is normalized by cell nuclei andresults are represented respect to cocultured basal control. Results ofpercentage of lipid content versus non-treated cells (basal control) areshowed in FIG. 7.

The results demonstrate that peptides PEP1 and PEP2 of the inventionincrease lipid accumulation in adipocytes when compared to basal controland old control.

Example 14

Preparation of a cream containing peptide PEP1 (Ac-Asp-Val-Tyr-Lys-NH₂)solution

In a suitable vessel, the ingredients of phase A: water [INCI: WATER(AQUA)], Zemea™ [INCI: PROPANEDIOL], Hydrolite® 5 [INCI: PENTYLENEGLYCOL], Phenoxetol™ [INCI: PHENOXYETHANOL] and Dissolvine® NA2 [INCI:DISODIUM EDTA] are dissolved.

Phase A1 ingredient: Carbopol® Ultrez 10 Polymer [INCI: CARBOMER] isadded to the previous mixture. Once dispersed, phase A2: Cola®Fax CPE-K[INCI: POTASSIUM CETYL PHOSPHATE] is introduced. Then the mixture isheated up to 70-75° C. In a separate vessel, phase B ingredients:Schercemol™ DIS Ester [INCI: DIISOPROPYL SEBACATE], Phytocream® 2000[INCI: GLYCERYL STEARATE, CETEARYL ALCOHOL, POTASSIUM PALMITOYLHYDROLYZED WHEAT PROTEIN], Massocare® EC [INCI: ETHYLHEXYL COCOATE],Astro-sil™ 2C 350 [INCI: DIMETHICONE] and Tocopheryl Acetate [INCI:TOCOPHERYL ACETATE] are mixed and the resulting mixture is heated at70-75° C.

The emulsion is made by adding slowly phase B into phase A underconditions of fast stirring with a turbine.

Once the mixture is cooled to 40° C., the components of phase C:November™ EC-1 polymer [INCI: MINERAL OIL (PARAFFINUM LIQUIDUM); WATER(AQUA); ACRYLATES/ACRYLAMIDE CROSSPOLYMER; POLYSORBATE 85] are added tothe previous mixture under stirring and mixed until dispersion.

Phase D: Peptide PEP1 solution [INCI: GLYCERIN; WATER (AQUA); peptidePEP1 is added to the previous mixture.

Phase E: Fragrance [INCI: FRAGANCE (PARFUM)], is added.

pH is adjusted to 6.0-6.5 with phase F ingredient sodium hydroxide 20%w/w [INCI: WATER (AQUA); SODIUM HYDROXIDE]).

TABLE 4 % Phase INGREDIENT (INCI name) weight A WATER 69.10 APROPANEDIOL 10.00 A PENTYLENE GLYCOL 2.00 A PHENOXYETHANOL 0.50 ADISODIUM EDTA 0.20 A1 CARBOMER 0.50 A2 POTASSIUM CETYL PHOSPHATE 0.50 BDIISOPROPYL SEBACATE 5.00 B [GLYCERYL STEARATE; CETEARYL ALCOHOL; 5.00POTASSIUM PALMITOYL HYDROLYZED WHEAT PROTEIN] B ETHYLHEXYL COCOATE 2.50B DIMETHICONE 1.00 B TOCOPHERYL ACETATE 0.50 C [MINERAL OIL (PARAFFINUMLIQUIDUM); 1.00 WATER (AQUA); ACRYLATES/ACRYLAMIDE CROSSPOLYMER;POLYSORBATE 85] D [GLYCERIN; WATER (AQUA); PEP1] 2.00 E FRAGANCE(PARFUM) 0.20 F [WATER (AQUA); SODIUM HYDROXIDE] q.s.

Preparation of a cream containing peptide PEP2(H-Ala-Leu-Lys-Pro-Asn-Thr-NH₂) solution

In a suitable vessel, the ingredients of phase A: water [INCI: WATER(AQUA)], Zemea™ [INCI: PROPANEDIOL], Hydrolite® 5 [INCI: PENTYLENEGLYCOL], Phenoxetol™ [INCI: PHENOXYETHANOL] and Dissolvine® NA2 [INCI:DISODIUM EDTA] are dissolved.

Phase A1 ingredient:Carbopol® Ultrez 10 Polymer [INCI: CARBOMER] isadded to the previous mixture. Once dispersed, phase A2: Cola®Fax CPE-K[INCI: POTASSIUM CETYL PHOSPHATE] is introduced. Then the mixture isheated up to 70-75° C.

In a separate vessel, phase B ingredients: Schercemol™ DIS Ester [INCI:DI ISOPROPYL SEBACATE], Phytocream® 2000 [INCI: GLYCERYL STEARATE,CETEARYL ALCOHOL, POTASSIUM PALMITOYL HYDROLYZED WHEAT PROTEIN],Massocare® EC [INCI: ETHYLHEXYL COCOATE], Astro-sil™ 2C 350 [INCI:DIMETHICONE] and Tocopheryl Acetate [INCI: TOCOPHERYL ACETATE] are mixedand the resulting mixture is heated at 70-75° C.

The emulsion is made by adding slowly phase B into phase A underconditions of fast stirring with a turbine.

Once the mixture is cooled to 40° C., the components of phase C:Novemer™ EC-1 polymer [INCI: MINERAL OIL (PARAFFINUM LIQUIDUM); WATER(AQUA); ACRYLATES/ACRYLAMIDE CROSSPOLYMER; POLYSORBATE 85] are added tothe previous mixture under stirring and mixed until dispersion.

Phase D: Peptide PEP2 solution [INCI: GLYCERIN; WATER (AQUA); peptidePEP2 is added to the previous mixture.

Phase E: Fragrance [INCI: FRAGANCE (PARFUM)], is added.

pH is adjusted to 6.0-6.5 with phase F ingredient sodium hydroxide 20%w/w [INCI: WATER (AQUA); SODIUM HYDROXIDE]).

TABLE 5 % Phase INGREDIENT (INCI name) weight A WATER 69.10 APROPANEDIOL 10.00 A PENTYLENE GLYCOL 2.00 A PHENOXYETHANOL 0.50 ADISODIUM EDTA 0.20 A1 CARBOMER 0.50 A2 POTASSIUM CETYL PHOSPHATE 0.50 BDIISOPROPYL SEBACATE 5.00 B [GLYCERYL STEARATE; CETEARYL ALCOHOL; 5.00POTASSIUM PALMITOYL HYDROLYZED WHEAT PROTEIN] B ETHYLHEXYL COCOATE 2.50B DIMETHICONE 1.00 B TOCOPHERYL ACETATE 0.50 C [MINERAL OIL (PARAFFINUMLIQUIDUM); 1.00 WATER (AQUA); ACRYLATES/ACRYLAMIDE CROSSPOLYMER;POLYSORBATE 85] D [GLYCERIN; WATER (AQUA); PEP2] 2.00 E FRAGANCE(PARFUM) 0.20 F [WATER (AQUA); SODIUM HYDROXIDE] q.s.

Example 15

Preparation of a Gel-cream comprising peptide PEP1(Ac-Asp-Val-Tyr-Lys-NH₂).

In a suitable vessel, the ingredients of phase A: water [INCI: WATER(AQUA)], Zemea™ [INCI: PROPANEDIOL], Phenoxetol® [INCI: PHENOXYETHANOL],Dissolvine® NA2 [INCI: DISODIUM EDTA] and Potassium Sorbate Granular[POTASSIUM SORBATE] are dispersed.

Phase A1 ingredient: Carbopol® Ultrez 21 Polymer [INCI: ACRYLATES/C10/30ALKYL ACRYLATE CROSSPOLYMER] is added to the previous mixture understirring. Once dispersed, phase A2: Xanthan Gum [INCI: XANTHAN GUM] isintroduced to the previous mixture and stirred until completedispersion.

In a separate vessel, phase B ingredients: Schercemol™ 1818 Ester [INCI:ISOSTEARYL ISOSTEARATE], is weighed.

The emulsion is made by adding slowly phase B into phase A underconditions of fast stirring with a turbine.

Phase C: Peptide PEP1 solution [INCI: WATER (AQUA); CAPRYLYL GLYCOL;Peptide PEP1 is added to the previous mixture.

pH is adjusted to 6.0-6.5 with phase D ingredient: Sodium Hydroxide 20%w/w [INCI: WATER (AQUA); SODIUM HYDROXIDE]).

TABLE 6 % Phase INGREDIENT (INCI name) weight A WATER 83.54 APROPANEDIOL 10.00 A PHENOXYETHANOL 0.35 A DISODIUM EDTA 0.20 A POTASSIUMSORBATE 0.10 A1 ACRYLATES/C10/30 ALKYL ACRYLATE 0.65 CROSSPOLYMER A2XANTHAN GUM 0.20 B ISOSTEARYL ISOSTEARATE 2.00 C [WATER (AQUA); CAPRYLYLGLYCOL; 2.00 PEPTIDE PEP1] D [WATER (AQUA); SODIUM HYDROXIDE] 0.96

A gel-cream comprising peptide PEP2 (H-Ala-Leu-Lys-Pro-Asn-Thr-NH₂) canbe obtained by substituting PEP2 for PEP1 in this example.

Example 16

Preparation of a gel comprising 2% of peptide PEP1(Ac-Asp-Val-Tyr-Lys-NH₂) solution

In a suitable vessel, the ingredients of phase A: water [INCI: WATER(AQUA)], Zemea™ [INCI: PROPANEDIOL], Glucam™E-20 Humectant [INCI: METHYLGLUCETH-20], Dissolvine® NA2 [INCI: DISODIUM EDTA], Phenoxetol® [INCI:PHENOXYETHANOL] are dissolved.

Phase A1: Carbopol® ultrez 10 polymer [INCI: CARBOMER] is added to theprevious mixture and mixed until complete dispersion.

Phase B: Peptide PEP-1 solution [INCI: WATER (AQUA); CAPRYLYL GLYCOL;PEP-1] is added to previous mixture and mixed.

Phase C: EUMULGIN® CO 40 [INCI: PEG-40 HYDROGENATED CASTOR OIL],Fragrance [INCI: FRAGRANCE (PARFUM)], is added to previous mixture andmixed.

The pH is adjusted to 6.0-6.5 with the ingredient of phase D: SodiumHydroxide 20% w/w [INCI: WATER (AQUA); SODIUM HYDROXIDE].

TABLE 7 % Phase INGREDIENT (INCI name) weight A WATER 80.8 A PROPANEDIOL10 A METHYL GLUCETH-20 5 A PHENOXYETHANOL 0.5 A DISODIUM EDTA 0.2 A1CARBOMER 0.7 B [WATER (AQUA); CAPRYLYL GLYCOL; 2 Peptide PEP1] C PEG-40HYDROGENATED CASTOR OIL 0.6 C FRAGRANCE (PARFUM) 0.2 D [WATER (AQUA);SODIUM HYDROXIDE] q.s.

A gel comprising peptide PEP2 (H-Ala-Leu-Lys-Pro-Asn-Thr-NH₂) can beobtained by substituting PEP2 for PEP1 in this example.

Example 17

Preparation of a lotion comprising 2% of peptide PEP1(Ac-Asp-Val-Tyr-Lys-NH₂) solution

In a suitable vessel, the ingredients of phase A1: water [INCI: WATER(AQUA)], Zemea™ [INCI: PROPANEDIOL], glycerin [INCI: GLYCERIN],potassium sorbate [INCI: POTASSIUM SORBATE] and Dissolvine® NA2 [INCI:DISODIUM EDTA] are dissolved.

Phase A2 ingredient: Carbopol® Ultrez 30 Polymer [INCI: CARBOMER] isadded in the previous mixture. Once dispersed, phase A3: xanthan gum[INCI: XANTHAN GUM] is introduced. Then the mixture is heated at 70-75°C.

In a separate vessel, phase B ingredients: Fancor® Meadowfoam seed oil[INCI: LIMNANTHES ALBA (MEADOWFOAM) SEED OIL], Kodasil™ 600 IDD Gel[INCI: ISODODECANE; VINYL DIMETHICONE/LAURYL DIMETHICONE CROSSPOLYMER;DIMETHICONE; LAURYL DIMETHICONE], Astro-sil™ 2C 350 [INCI: DIMETHICONE],Schercemol™ CATC ester [INCI: COCOYL ADIPIC ACID/TRIMETHYLOLPROPANECOPOLYMER; TRIMETHYLOLPROPANE], Schercemol™ DIS ester [INCI: DIISOPROPYLSEBACATE], Tocopheryl Acetate [INCI: TOCOPHERYL ACETATE] and Phenoxetol™[INCI: PHENOXYETHANOL] are mixed and the resulting mixture is heated at70-75° C.

The emulsion is made by adding slowly phase B into phase A underconditions of fast stirring with a turbine.

Once the mixture is cooled to 40° C., the components of phase C:Novemer™ EC-2 polymer [INCI: WATER (AQUA); SODIUM ACRYLATES/BEHENETH-25METHACRYLATE CROSSPOLYMER; HYDROGENATED POLYDECENE, LAURYL GLUCOSIDE],SA-SB-300 (7%) [INCI: SILICA; DIMETHICONE], Fragrance [INCI: FRAGANCE(PARFUM)], and peptide PEP1 solution [INCI: WATER (AQUA); CAPRYLYLGLYCOL; peptide PEP1) are added to the previous mixture.

pH is adjusted to 6.0-6.5 with phase D ingredient sodium hydroxide 20%w/w [INCI: WATER (AQUA); SODIUM HYDROXIDE]).

TABLE 8 % Phase INGREDIENT (INCI name) weight A1 WATER 63.60 A1PROPANEDIOL 10.00 A1 GLYCERIN 5.00 A1 POTASSIUM SORBATE 0.10 A1 DISODIUMEDTA 0.20 A2 CARBOMER 0.30 A3 XANTHAN GUM 0.20 B LIMNANTHES ALBA(MEADOWFOAM) SEED OIL 5.00 B [ISODODECANE; VINYL DIMETHICONE/LAURYLDIMETHICONE CROSSPOLYMER; 3.00 DIMETHICONE; LAURYL DIMETHICONE] BDIMETHICONE 3.00 B [COCOYL ADIPIC ACID/TRIMETHYLOLPROPANE 2.00COPOLYMER; TRIMETHYLOLPROPANE] B DIISOPROPYL SEBACATE 2.00 B TOCOPHERYLACETATE 0.50 B PHENOXYETHANOL 0.50 C [WATER (AQUA); SODIUM 1.50ACRYLATES/BEHENETH-25 METHACRYLATE CROSSPOLYMER; HYDROGENATEDPOLYDECENE, LAURYL GLUCOSIDE] C [SILICA; DIMETHICONE] 1.00 C [WATER(AQUA); CAPRYLYL 2.00 GLYCOL; Peptide PEP1] C FRAGANCE (PARFUM) 0.10 D[WATER (AQUA); SODIUM HYDROXIDE] q.s.

A lotion comprising peptide PEP2 (H-Ala-Leu-Lys-Pro-Asn-Thr-NH₂) can beobtained by substituting PEP2 for PEP1 in this example.

Example 18

Preparation of a fluid emulsion comprising 2% of peptide PEP1(Ac-Asp-Val-Tyr-Lys-NH₂) solution

In a suitable vessel, the ingredients of phase A1: water [INCI: WATER(AQUA)], Zemea™ [INCI: PROPANEDIOL], glycerin [INCI: GLYCERIN],Genencare™ OSMS BA [INCI: BETAINE], Dissolvine® NA2 [INCI: DISODIUMEDTA], potassium sorbate [INCI: POTASSIUM SORBATE] are dissolved.

Phase A2: Carbopol® Ultrez 10 polymer [INCI: CARBOMER] is added to theprevious mixture. Once dispersed, phase A3: Cola®Fax CPE-K [INCI:POTASSIUM CETYL PHOSPHATE] is added. The resulting mixture is heated at70-75° C.

In another vessel, the components of phase B: Massocare® HD [INCI:ISOHEXADECANE], Lincol™ BAS [INCI: C12-15 ALKYL BENZOATE], Gandak™ C[INCI: CETYL ALCOHOL], Sorbital™ T 20 P [INCI: POLYSORBATE 20],2-phenoxyethanol [INCI: PHENOXYETHANOL], Vegetable stearic acid 50/50[INCI: STEARIC ACID; PALMITIC ACID] are mixed and heated at 70-75° C.Phase B is slowly introduced over phase A under conditions of intensestirring with a turbine.

The mixture is cooled at 40° C., and phase C: BRB™ CM 56-S [INCI:CYCLOMETHICONE], peptide PEP1 solution [INCI: WATER (AQUA); CAPRYLYLGLYCOL; peptide PEP1], Fragrance [INCI: FRAGRANCE (PARFUM)] is added.The pH is adjusted to 6.0-6.5 with the ingredient of phase D: SodiumHydroxide 20% w/w [INCI: WATER (AQUA); SODIUM HYDROXIDE].

TABLE 9 % Phase INGREDIENT (INCI name) weight A1 WATER 71.2 A1PROPANEDIOL 10 A1 GLYCERIN 3 A1 BETAINE 3 A1 DISODIUM EDTA 0.2 A1POTASSIUM SORBATE 0.1 A2 CARBOMER 0.4 A3 POTASSIUM CETYL PHOSPHATE 0.4 BISOHEXADECANE 2 B C12-15 ALKYL BENZOATE 2 B CETYL ALCOHOL 1.8 BPOLYSORBATE 20 0.8 B PHENOXYETHANOL 0.5 B [STEARIC ACID; PALMITIC ACID]0.5 C CYCLOMETHICONE 2 C [WATER (AQUA); 2 CAPRYLYL GLYCOL; PEP1] CFRAGRANCE (PARFUM) 0.1 D [WATER (AQUA); SODIUM HYDROXIDE] q.s.

A fluid emulsion comprising peptide PEP2 (H-Ala-Leu-Lys-Pro-Asn-Thr-NH₂)can be obtained by substituting PEP2 for PEP1 in this example.

Example 19

In vitro quantification of Muscle bind like protein 1 (MBNL1) in humanskeletal muscle cells by Time resolved fluorescence resonance energytransfer.

Different peptides of the invention are tested as disclosed in Example 7at 0.5 mg/mL. Results are shown in Table 10 and demonstrate that all thepeptides increase MBNL1 levels when compared to the basal control.

TABLE 10 % Identifier Compound MBNL1 PEP3 Palm-Asp-Val-Tyr-Lys-NH₂ 127.7PEP4 Ac-Asp-Val-Tyr-Lys-OH 378.5 PEP5 H-Asp-Val-Tyr-Lys-NH₂ 261.4 PEP7Ac-Glu-Val-Tyr-Lys-NH₂ 141.5 PEP8 Ac-Asp-Ile-Tyr-Lys-NH₂ 190.4 PEP9Ac-Asp-Val-Phe-Lys-NH₂ 134.2 PEP10 Ac-Asp-Val-Tyr-Arg-NH₂ 158.3 PEP11Ac-Asn-Val-Tyr-Lys-NH₂ 145.2 PEP12 Ac-Asp-Leu-Tyr-Lys-NH₂ 154.4 PEP13Palm-Glu-Val-Tyr-Lys-NH₂ 147.2 PEP14 Ac-Ala-Asp-Val-Tyr-Lys-NH₂ 145.0PEP15 Ac-Asp-Val-Tyr-Lys-Ala-NH₂ 145.2 PEP20 Ac-Glu-Ile-Tyr-Lys-NH₂214.2 PEP23 Ac-Glu-Ile-Tyr-Arg-NH₂ 181.4 PEP24 Ac-Glu-Ile-Phe-Arg-NH₂117.5

Example 20

In vitro quantification of Muscle bind like protein 1 (MBNL1) in humanskeletal muscle cells by Time resolved fluorescence resonance energytransfer.

The assay is performed as disclosed in Example 7 except that hSkMc fromTEBU-BIO (Barcelona, Spain) are used. Different peptides of theinvention are tested at a concentration of 0.5 mg/ml.

Results are shown in Table 11 and demonstrate that all the peptidesincrease MBNL1 levels when compared to the basal control.

TABLE 11 % Identifier Compound MBNL1 PEP27 Ac-Ala-Leu-Lys-Pro-Asn-Thr-OH126.1 PEP30 H-Ala-Leu-Arg-Pro-Asn-Thr-NH₂ 181.3 PEP31H-Ala-Leu-Lys-Val-Asn-Thr-NH₂ 120.0 PEP40 H-Leu-Lys-Pro-Asn-Thr-NH₂117.3 PEP41 H-Ala-Leu-Lys-Pro-Asn-NH₂ 138.4 PEP42H-Gly-Ile-Lys-Pro-Asn-Thr-NH₂ 114.2 PEP44 H-Ala-Ile-Arg-Pro-Asn-Thr-NH₂240.6 PEP46 H-Gly-Val-Arg-Pro-Asn-Thr-NH₂ 182.1 PEP50H-Ala-Leu-Lys-Pro-Gln-Thr-NH₂ 119.4

Example 21

In vivo study with a composition comprising PEP1, for the assessment ofantiwrinkle and smoothing efficacy of long-term application in Caucasianskin type female volunteers.

The study is carried out for 28 days. Forty-two (42) Caucasian femalevolunteers, aged between 35 and 58 years-old showing skin wrinklednesson the crow's feet area are included. Subjects apply a cream comprisingPEP1 (ACTIVE cream) on one side of the face (left or right) and aplacebo cream having the same composition except PEP1 (PLACEBO cream).Both creams are applied for 28 days twice a day (morning and evening).The subjects serve as their own reference and results obtained at time28 days are compared with those obtained at initial time and betweentreatments (ACTIVE vs PLACEBO).

The antiwrinkle efficacy of the creams in crow's feet area is assessedby the determination of the maximum depth of biggest wrinkle: Images ofvolunteer's crow's feet area are measured with a 3D microtopographyimaging system. Volunteers are instructed to remain in smilingexpression and the maximum depth of the biggest wrinkle is taken atinitial time and after 28 days of product application. Results ofwrinkle reduction after treatment are shown in Table 12.

TABLE 12 % of reduction at 28 days Active Cream 4.8 Placebo Cream 1.6

Results show that after 28 days of application of the creams there is areduction of the maximum depth of the biggest wrinkle compared toinitial time. Said reduction is much higher for ACTIVE cream thanPLACEBO cream.

The smoothing efficacy of the creams is assessed by determining thearithmetic roughness (Sa): Images of volunteer's cheek are taken with a3D microtopography imaging system. Arithmetic roughness (Sa)measurements are taken at initial time and after 28 days of creamapplication. Results of roughness reduction after treatment are shown inTable 13.

TABLE 13 % of reduction at 28 days Active Cream 3.3 Placebo Cream 0.3

Results show that there is a reduction of arithmetic roughness (Sa)after treatment with ACTIVE cream whereas this effect is negligible withPLACEBO cream. Roughness reduction implies that the skin is smoother.

1. A compound of formula (I)R₁-W_(m)-X_(n)-AA₁-AA₂-AA₃-AA₄-AA₅-AA₆-Y_(p)-Z_(q)-R₂   (I), or astereoisomer and/or cosmetically acceptable salt thereof, wherein: AA₁is Asp, Glu, Asn, Gln, Ala, Gly or no amino acid; AA₂ is Val, Ile, Leuor Ala; AA₃ is Tyr, Phe, Trp, Lys, Arg or His; AA₄ is Lys, Arg, His, Proor Val; AA₅ is Asn, Asp, Gin or no amino acid; AA₆ is Thr, Ala, Ser orno amino acid; W, X, Y and Z are each independently any amino acid; m,n, p and q are each independently 0 or 1; m+n+p+q is less than or equalto 2; R₁ is selected from the group consisting of H, a polymer derivedfrom polyethylene glycol, a non-cyclic aliphatic group, alicyclyl,heterocyclyl, heteroarylalkyl, aryl, aralkyl and R₅—CO—, wherein R₅ isselected from the group consisting of H, a non-cyclic aliphatic group,alicyclyl, aryl, aralkyl, heterocyclyl and heteroarylalkyl; R₂ isselected from the group consisting of —NR₃R₄, —OR₃, —SR₃, wherein R₃ andR₄ are independently selected from a group consisting of H, a polymerderived from polyethylene glycol, a non-cyclic aliphatic group,alicyclyl, heterocyclyl, heteroarylalkyl, aryl and aralkyl; and R₁ andR₂ are not amino acids.
 2. A compound according to claim 1, wherein whenAA₅ is no amino acid, AA₁ is Asp, Glu, Asn or Gln; AA₂ is Val, Ile, Leuor Ala; AA₃ is Tyr, Phe or Trp; AA₄ is Lys, Arg or His; AA₆ is no aminoacid, and/or wherein when AA₅ is Asn, Asp or Gln, AA₁ is Ala, Gly or noamino acid; AA₂ is Val, Ile or Leu; AA₃ is Lys, Arg or His; AA₄ is Proor Val; AA₆ is Thr, Ala, Ser or no amino acid; and AA₁ is different fromAA₆.
 3. A compound according to claim 2, wherein AA₁ is Asp, Glu, Asn orGln; AA₂ is Val, Ile, Leu or Ala; AA₃ is Tyr, Phe or Trp; AA₄ is Lys,Arg or His; AA₅ is no amino acid; and AA₆ is no amino acid.
 4. Acompound according to claim 3, wherein: (i) AA₁ is Asp, Glu or Asn, orwherein (ii) AA₁ is Asp or Glu; and/or (ii) wherein AA₂ is Val or Ile;and/or (iii) wherein AA₃ is Tyr or Phe; and/or (iv) wherein AA₄ is Lysor Arg.
 5. (canceled)
 6. (canceled)
 7. (canceled)
 8. A compoundaccording to claim 3, wherein AA₁ is Asp; AA₂ is Val; AA₃ is Tyr; andAA₄ is Lys.
 9. A compound according to claim 2, wherein AA₁ is Ala, Glyor no amino acid; AA₂ is Val, Ile or Leu; AA₃ is Lys, Arg or His; AA₄ isPro or Val; AA₅ is Asn, Asp or Gln; AA₆ is Thr, Ala, Ser or no aminoacid; and AA₁ is different from AA₆.
 10. A compound according to claim9, wherein: (i) AA₁ is Ala or Gly; and/or (ii) AA₂ is Leu or Ile; and/or(iii) AA₃ is Lys or Arg; and/or (iv) AA₅ is Asn or Asp; and/or (v) AA₆is Thr, Ala or Ser, or AA₆ is Thr or Ala.
 11. (canceled)
 12. (canceled)13. (canceled)
 14. (canceled)
 15. A compound according to claims 9,wherein AA₁ is Ala; AA₂ is Leu; AA₃ is Lys; AA₄ is Pro; AA₅ is Asn; andAA₆ is Thr.
 16. A compound according to claim 1, wherein m+n+p+q is 0or
 1. 17. (canceled)
 18. A compound according to claim 1, wherein thecompound is selected from the group consisting of:(R₁-[SEQ ID NO. 1]-R₂) R₁-Asp-Val-Tyr-Lys-R₂; (R₁-[SEQ ID NO. 2]-R₂)R₁-Ala-Leu-Lys-Pro-Asn-Thr-R₂; (R₁-[SEQ ID NO. 3]-R₂)R₁-Glu-Val-Tyr-Lys-R₂; (R₁-[SEQ ID NO. 4]-R₂) R₁-Asp-Ile-Tyr-Lys-R₂;(R₁-[SEQ ID NO. 5]-R₂) R₁-Asp-Val-Phe-Lys-R₂; (R₁-[SEQ ID NO. 6]-R₂)R₁-Asp-Val-Tyr-Arg-R₂; (R₁-[SEQ ID NO. 7]-R₂) R₁-Asn-Val-Tyr-Lys-R₂;(R₁-[SEQ ID NO. 8]-R₂) R₁-Asp-Leu-Tyr-Lys-R₂; (R₁-[SEQ ID NO. 9]-R₂)R₁-Ala-Asp-Val-Tyr-Lys-R₂; (R₁-[SEQ ID NO. 10]-R₂)R₁-Asp-Val-Tyr-Lys-Ala-R₂; (R₁-[SEQ ID NO. 15]-R₂)R₁-Glu-Ile-Tyr-Lys-R₂; (R₁-[SEQ ID NO. 18]-R₂) R₁-Glu-Ile-Tyr-Arg-R₂;(R₁-[SEQ ID NO. 19]-R₂) R₁-Glu-Ile-Phe-Arg-R₂; (R₁-[SEQ ID NO. 22]-R₂)R₁-Ala-Leu-Arg-Pro-Asn-Thr-R₂; (R₁-[SEQ ID NO. 23]-R₂)R₁-Ala-Leu-Lys-Val-Asn-Thr-R₂; (R₁-[SEQ ID NO. 30]-R₂)R₁-Leu-Lys-Pro-Asn-Thr-R₂; (R₁-[SEQ ID NO. 31]-R₂)R₁-Ala-Leu-Lys-Pro-Asn-R₂; (R₁-[SEQ ID NO. 32]-R₂)R₁-Gly-Ile-Lys-Pro-Asn-Thr-R₂; (R₁-[SEQ ID NO. 34]-R₂)R₁-Ala-Ile-Arg-Pro-Asn-Thr-R₂; (R₁-[SEQ ID NO. 34]-R₂)R₁-Gly-Val-Arg-Pro-Asn-Thr-R₂; (R₁-[SEQ ID NO. 40]-R₂)R1-Ala-Leu-Lys-Pro-Gln-Thr-R₂;

and combinations thereof.
 19. A compound according to claim 1, whereinR₁ is selected from the group consisting of H and R₅—CO—, wherein R₅ isselected from the group consisting of C₁-C₁₈ alkyl, C₂-C₂₄ alkenyl,C₃-C₂₄ cycloalkyl; and R₂ is —NR₃R₄ or —OR₃ wherein R₃ and R₄ areindependently selected from the group consisting of H and C₁-C₁₆ alkyl.20. A compound according to claim 1, wherein the compound is selectedfrom the group consisting of: (IV)Ac-W_(m)-X_(n)-Asp-Val-Tyr-Lys-Y_(p)-Z_(q)-NH₂; (V)H-W_(m)-X_(n)-Ala-Leu-Lys-Pro-Asn-Thr-Y_(p)-Z_(q)-NH₂;(PEP1, Ac-[SEQ ID NO. 1]-NH₂) Ac-Asp-Val-Tyr-Lys-NH₂;(PEP2, H-[SEQ ID NO. 2]-NH₂) H-Ala-Leu-Lys-Pro-Asn-Thr-NH₂-;

and combinations thereof.
 21. A compound according to claim 1, whereinthe compound is selected from the group consisting of:(PEP3, Palm-[SEQ ID NO. 1]-NH₂) Palm-Asp-Val-Tyr-Lys-NH₂;(PEP4, Ac-[SEQ ID NO. 2]-OH) Ac-Asp-Val-Tyr-Lys-OH;(PEP5, H-[SEQ ID NO. 2]-NH₂) H-Asp-Val-Tyr-Lys-NH₂;(PEP7, Ac-[SEQ ID NO. 3]-NH₂) Ac-Glu-Val-Tyr-Lys-NH₂;(PEP8, Ac-[SEQ ID NO. 4]-NH₂) Ac-Asp-Ile-Tyr-Lys-NH₂;(PEP9, Ac-[SEQ ID NO. 5]-NH₂) Ac-Asp-Val-Phe-Lys-NH₂;(PEP10, Ac-[SEQ ID NO. 6]-NH₂) Ac-Asp-Val-Tyr-Arg-NH₂;(PEP11, Ac-[SEQ ID NO. 7]-NH₂) Ac-Asn-Val-Tyr-Lys-NH₂;(PEP12, Ac-[SEQ ID NO. 8]-NH₂) Ac-Asp-Leu-Tyr-Lys-NH₂;(PEP13, Palm-[SEQ ID NO. 3]-NH₂) Palm-Glu-Val-Tyr-Lys-NH₂;(PEP14, Ac-[SEQ ID NO. 9]-NH₂) Ac-Ala-Asp-Val-Tyr-Lys-NH₂;(PEP15, Ac-[SEQ ID NO. 10]-NH₂) Ac-Asp-Val-Tyr-Lys-Ala-NH₂;(PEP20, Ac-[SEQ ID NO. 15]-NH₂) Ac-Glu-Ile-Tyr-Lys-NH₂;(PEP23, Ac-[SEQ ID NO. 18]-NH₂) Ac-Glu-Ile-Tyr-Arg-NH₂;(PEP24, Ac-[SEQ ID NO. 19]-NH₂) Ac-Glu-Ile-Phe-Arg-NH₂;(PEP27, Ac-[SEQ ID NO. 2]-OH) Ac-Ala-Leu-Lys-Pro-Asn-Thr-OH;(PEP30, H-[SEQ ID NO. 22]-NH₂) H-Ala-Leu-Arg-Pro-Asn-Thr-NH₂;(PEP31, H-[SEQ ID NO. 23]-NH₂) H-Ala-Leu-Lys-Val-Asn-Thr-NH₂;(PEP40, H-[SEQ ID NO. 30]-NH₂) H-Leu-Lys-Pro-Asn-Thr-NH₂;(PEP41, H-[SEQ ID NO. 31]-NH₂) H-Ala-Leu-Lys-Pro-Asn-NH₂;(PEP42, H-[SEQ ID NO. 32]-NH₂) H-Gly-Ile-Lys-Pro-Asn-Thr-NH₂;(PEP44, H-[SEQ ID NO. 34]-NH₂) H-Ala-Ile-Arg-Pro-Asn-Thr-NH₂;(PEP46, H-[SEQ ID NO. 36]-NH₂) H-Gly-Val-Arg-Pro-Asn-Thr-NH₂;(PEP50, H-[SEQ ID NO. 40]-NH₂) H-Ala-Leu-Lys-Pro-Gln-Thr-NH₂-);

and combinations thereof.
 22. A combination of a compound according toclaim 1 and at least one of Botulinum toxin and the peptide of sequenceAc-Glu-Glu-Met-Gln-Arg-Arg-NH₂ (Ac-[SEQ ID NO. 41]-NH₂.
 23. Acomposition comprising a cosmetically effective quantity of a compoundof claim 1, and at least one cosmetically acceptable excipient oradjuvant.
 24. (canceled)
 25. (canceled)
 26. (canceled)
 27. (canceled)28. A method of treatment and/or care of the skin, hair, nails and/ormucous membranes of a subject comprising administering a compoundaccording to claim 1 to the skin, hair, nails and/or mucous membranesthe subject.
 29. The method according to claim 28, wherein the treatmentand/or care comprises at least one of: a treatment of skin aging; areduction of skin wrinkles; a stimulation of collagen synthesis; areduction of collagen loss; an improvement or maintenance of skinfirmness; a treatment of sagging appearance of the skin; a reduction offacial asymmetry; an increase of the volume of adipose tissue; analleviation of adipose tissue loss; a reduction of skin roughness; andan improvement in skin smoothness.